Sample records for human hypoxanthine phosphoribosyltransferase

  1. SHORT COMMUNICATION Rat Hypoxanthine Phosphoribosyltransferase cDNA

    E-print Network

    Monnat, Ray

    SHORT COMMUNICATION Rat Hypoxanthine Phosphoribosyltransferase cDNA Cloning and Sequence Analysis, 1991 We have determined the nucleotide sequence.of the rat hprt (hypoxanthine phoephorihosyltransferase oligonucleotide primer pair for efficient PCR amplification of the rat hprf coding region. These sequencedata

  2. Hypoxanthine guanine phosphoribosyltransferase (HGPRT) in Gilles de la Tourette syndrome.

    PubMed

    Merril, C R; Leavitt, J; Van Keuren, M L; Ebert, M H; Caine, E D

    1979-01-01

    Hypoxanthine guanine phosphoribosyltransferase (HGPRT) and adenosine phosphoribosyltransferase (APRT) were examined from 11 individuals with Gilles de la Tourette syndrome, 10 of their first- or second-degree relatives, and 3 normal controls. It has been suggested that in some self-mutilating Tourette patients, HGPRT shows a time-related loss of activity at 4 degrees C, and an unusual isoelectrofocusing pattern. Although 3 patients experienced self-mutilation, no consistent abnormalities were found in the temperature-stability of their HGPRT at 4 degrees C and 70 degrees C, or in isoelectrofocusing of HGPRT purified by immunoprecipitation. An alteration of the purine metabolic pathway in Tourette syndrome has not been established. PMID:284202

  3. Cloning and expression of the hypoxanthine-guanine phosphoribosyltransferase gene from Trypanosoma brucei.

    PubMed Central

    Allen, T E; Ullman, B

    1993-01-01

    The hypoxanthine-guanine phosphoribosyltransferase (HGPRT) enzyme of Trypanosoma brucei and related parasites provides a rational target for the treatment of African sleeping sickness and several other parasitic diseases. To characterize the T. brucei HGPRT enzyme in detail, the T. brucei hgprt was isolated within a 4.2 kb SalI-KpnI genomic insert and sequenced. Nucleotide sequence analysis revealed an open reading frame of 630 bp that encoded a protein of 210 amino acids with a M(r) = 23.4 kd. After gap alignment, the T. brucei HGPRT exhibited 21-23% amino acid sequence identity, mostly in three clustered regions, with the HGPRTs from human, S. mansoni, and P falciparum, indicating that the trypanosome enzyme was the most divergent of the group. Surprisingly, the T. brucei HGPRT was more homologous to the hypoxanthine phosphoribosyltransferase (HPRT) from the prokaryote V. harveyi than to the eukaryotic HGPRTs. Northern blot analysis revealed two trypanosome transcripts of 1.4 and 1.9 kb, each expressed to equivalent degrees in insect vector and mammalian forms of the parasite. The T. brucei hgprt was inserted into an expression plasmid and transformed into S phi 606 E. coli that are deficient in both HPRT and xanthine-guanine phosphoribosyltransferase activities. Soluble, enzymatically active recombinant T. brucei HGPRT was expressed to high levels and purified to homogeneity by GTP-agarose affinity chromatography. The purified recombinant enzyme recognized hypoxanthine, guanine, and allopurinol, but not xanthine or adenine, as substrates and was inhibited by a variety of nucleotide effectors. The availability of a molecular clone encoding the T. brucei hgprt and large quantities of homogeneous recombinant HGPRT enzyme provides an experimentally manipulable molecular and biochemical system for the rational design of novel therapeutic agents for the treatment of African sleeping sickness and other diseases of parasitic origin. Images PMID:8265360

  4. A review of the molecular basis of hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency

    Microsoft Academic Search

    Donna G. Sculley; Paul A. Dawson; Bryan T. Emmerson; Ross B. Gordon

    1992-01-01

    Hypoxanthine-guanine phosphoribosyltransferase (HPRT, EC 2.4.2.8) is a purine salvage enzyme that catalyses the conversion of hypoxanthine and guanine to their respective mononucleotides. Partial deficiency of this enzyme can result in the overproduction of uric acid leading to a severe form of gout, whilst a virtual absence of HPRT activity causes the Lesch-Nyhan syndrome which is characterised by hyperuricaemia, mental retardation,

  5. Cloning and expression of the hypoxanthine-guanine phosphoribosyltransferase from Leishmania donovani

    Microsoft Academic Search

    Thomas E. Allen; Ho-Yon Hwang; Armando Jardim; Robert Olafson; Buddy Ullman

    1995-01-01

    The gene encoding the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) enzyme from Leishmania donovani has been cloned and sequenced. The hgprt open reading frame encoded a polypeptide of 211 amino acids that exhibited 3 regions of significant homology with other eukaryotic HGPRTs and a C-terminal tripeptide compatible with a glycosomal targeting signal. Northern blot analysis of L. donovani RNA revealed two hgprt transcripts,

  6. Hypoxanthine-guanine phosphoribosyltransferase. Characterization of a mutant in a patient with gout.

    PubMed Central

    Fox, I H; Dwosh, I L; Marchant, P J; Lacroix, S; Moore, M R; Omura, S; Wyhofsky, V

    1975-01-01

    The mutation in a young gouty male with a partial deficiency of hypoxanthine-guanine phosphoribosyltransferase has been evaluated. The serum uric acid was 11.8 mg/100 ml, and the urinary uric acid excretion was 1,279 mg/24 h. Erythrocyte hypoxanthine-guanine phosphoribosyltransferase was 34.2 nmol/h/mg, adenine phosphoribosyltransferase was 36.5 nmol/h/mg and phosphoribosylpyrophosphate was 2.6 muM. Hypoxanthine-guanine phosphoribosyltransferase from peripheral leukocytes and cultured diploid skin fibroblasts was within the normal range, but enzyme activity in rectal mucosa was below the normal range. Initial velocity studies of the normal enzyme and the mutant enzyme from erythrocytes with the substrates hypoxanthine, guanine, or phosphoribosylpyrophosphate showed that the Michaelis constants were similar. Product inhibition studies distinguished the mutant enzyme from the normal enzyme. Hyperbolic kinetics with increasing phosphoribosylpyrophosphate were converted to sigmoid kinetics by 0.2 mM GMP with the mutant enzyme but not with the normal enzyme. The mutant erythrocyte hypoxanthine-guanine phosphoribosyltransferase was inactivated normally at 80 degrees C and had a normal half-life in the peripheral circulation. The mol wt of 48,000 was similar to the normal enzyme mol wt of 47,000. With isoelectric focusing, the mutant erythrocyte enzyme had two major peaks with isoelectric pH's of 5.50 and 5.70, in contrast to the isoelectric pH's of 5.76, 5.82, and 6.02 of the normal isozymes. Isoelectric focusing of leukocyte extracts from the patient revealed the presence of the mutant enzyme. Cultured diploid fibroblasts from the propositus appeared to function normally, as shown by the inability to grow in 50-100 muM azaguanine and by the normal incorporation of [14C]hypoxanthine into nucleic acid. In contrast, erythrocytes from the patient displayed abnormal properties, including the increased synthesis of phosphoribosylphyrophosphate and elevated functional activity of orotate phosphoribosyltransferase and orotidylic decarboxylase. These unique kinetic, physical, and functional properties provide support for heterogeneous structural gene mutations in partial deficiencies of hypoxanthine-guanine phosphoribosyltransferase. PMID:1184748

  7. Hypoxanthine–guanine phosphoribosyltransferase from Mycobacterium tuberculosis H37Rv: Cloning, expression, and biochemical characterization

    Microsoft Academic Search

    Gisele Biazus; Cristopher Z. Schneider; Mario S. Palma; Luiz A. Basso; Diógenes S. Santos

    2009-01-01

    Human tuberculosis (TB) is a major cause of morbidity and mortality worldwide, especially in poor and developing countries. Moreover, the emergence of Mycobacterium tuberculosis strains resistant to first- and second-line anti-TB drugs raises the prospect of virtually incurable TB. Enzymes of the purine phosphoribosyltransferase (PRTase) family are components of purine salvage pathway and have been proposed as drug targets for

  8. Effect of 6-thioguanine on Chlamydia trachomatis growth in wild-type and hypoxanthine-guanine phosphoribosyltransferase-deficient cells.

    PubMed Central

    Qin, B; McClarty, G

    1992-01-01

    Chlamydiae have evolved a biphasic life cycle to facilitate their survival in two discontinuous habitats. The unique growth cycle is represented by two alternating forms of the organism, the elementary body and the reticulate body. Chlamydiae have an absolute nutritional dependency on the host cell to provide ribonucleoside triphosphates and other essential intermediates of metabolism. This report describes the pleiotropic effects of the purine antimetabolite 6-thioguanine on chlamydial replication. In order to display cytotoxicity, 6-thioguanine must first be converted to the nucleotide level by the host cell enzyme hypoxanthine-guanine phosphoribosyltransferase. Our results show that 6-thioguanine is an effective inhibitor of chlamydial growth with either wild-type or hypoxanthine-guanine phosphoribosyltransferase-deficient cell lines as the host. Interestingly, the mechanism of 6-thioguanine-induced inhibition of chlamydial growth is different depending on which cell line is used. With wild-type cells as the host, the cytotoxic effects of 6-thioguanine on chlamydial growth are relatively fast and irreversible. Under these circumstances, cytotoxicity likely results from the combined effect of starving chlamydiae for purine ribonucleotides and incorporation of host-derived 6-thioguanine-containing nucleotides into chlamydial nucleic acids. With hypoxanthine-guanine phosphoribosyltransferase-deficient cells as the host, 6-thioguanine must be present at the start of the chlamydial infection cycle to be effective and the growth inhibition is reversible upon removal of the antimetabolite. These findings suggest that in hypoxanthine-guanine phosphoribosyltransferase-deficient cells, the free base 6-thioguanine may inhibit the differentiation of elementary bodies to reticulate bodies. With hypoxanthine-guanine phosphoribosyltransferase-deficient cells as the host, 6-thioguanine was used as a selective agent in culture to isolate a Chlamydia trachomatis isolate resistant to the effects of the drug. This drug resistant C. trachomatis isolate was completely resistant to 6-thioguanine in hypoxanthine-guanine phosphoribosyltransferase-deficient cells; however, it displayed wildtype sensitivity to 6-thioguanine when cultured in wild-type host cells. PMID:1569017

  9. Crystallization of human nicotinamide phosphoribosyltransferase

    PubMed Central

    Takahashi, Ryo; Nakamura, Shota; Yoshida, Takuya; Kobayashi, Yuji; Ohkubo, Tadayasu

    2007-01-01

    In the NAD biosynthetic pathway, nicotinamide phosphoribosyltransferase (NMPRTase; EC 2.4.2.12) plays an important role in catalyzing the synthesis of nicotinamide mononucleotide from nicotinamide and 5?-phosphoribosyl-1?-­pyrophosphate. Because the diffraction pattern of the initally obtained crystals was not suitable for structure analysis, the crystal quality was improved by successive use of the microseeding technique. The resultant crystals diffracted to 2.0?Å resolution. These crystals belonged to space group P21, with unit-cell parameters a = 60.56, b = 106.40, c = 82.78?Å. Here, the crystallization of human NMPRTase is reported in the free form; the crystals should be useful for inhibitor-soaking experiments on the enzyme. PMID:17565174

  10. Crystal structure of human nicotinic acid phosphoribosyltransferase

    PubMed Central

    Marletta, Ada Serena; Massarotti, Alberto; Orsomando, Giuseppe; Magni, Giulio; Rizzi, Menico; Garavaglia, Silvia

    2015-01-01

    Nicotinic acid phosphoribosyltransferase (EC 2.4.2.11) (NaPRTase) is the rate-limiting enzyme in the three-step Preiss–Handler pathway for the biosynthesis of NAD. The enzyme catalyzes the conversion of nicotinic acid (Na) and 5-phosphoribosyl-1-pyrophosphate (PRPP) to nicotinic acid mononucleotide (NaMN) and pyrophosphate (PPi). Several studies have underlined the importance of NaPRTase for NAD homeostasis in mammals, but no crystallographic data are available for this enzyme from higher eukaryotes. Here, we report the crystal structure of human NaPRTase that was solved by molecular replacement at a resolution of 2.9 Å in its ligand-free form. Our structural data allow the assignment of human NaPRTase to the type II phosphoribosyltransferase subfamily and reveal that the enzyme consists of two domains and functions as a dimer with the active site located at the interface of the monomers. The substrate-binding mode was analyzed by molecular docking simulation and provides hints into the catalytic mechanism. Moreover, structural comparison of human NaPRTase with the other two human type II phosphoribosyltransferases involved in NAD biosynthesis, quinolinate phosphoribosyltransferase and nicotinamide phosphoribosyltransferase, reveals that while the three enzymes share a conserved overall structure, a few distinctive structural traits can be identified. In particular, we show that NaPRTase lacks a tunnel that, in nicotinamide phosphoribosiltransferase, represents the binding site of its potent and selective inhibitor FK866, currently used in clinical trials as an antitumoral agent.

  11. Germ-line transmission of a planned alteration made in a hypoxanthine phosphoribosyltransferase gene by homologous recombination in embryonic stem cells.

    PubMed Central

    Koller, B H; Hagemann, L J; Doetschman, T; Hagaman, J R; Huang, S; Williams, P J; First, N L; Maeda, N; Smithies, O

    1989-01-01

    Embryonic stem cells (derived from 129/Ola mice) containing a mutant hypoxanthine phosphoribosyltransferase gene that had been corrected in vitro in a planned manner by homologous recombination were injected into blastocysts obtained from C57BL/6J mice. The injected blastocysts were introduced into pseudopregnant female mice to complete their development. Eleven surviving pups were obtained. Nine were chimeras: six males and three females. Two of the males transmitted the embryonic stem cell genome containing the alteration in the hypoxanthine phosphoribosyltransferase gene to their offspring at high frequencies. These experiments demonstrate that a preplanned alteration in a chosen gene can be made in the germ line of an experimental animal by homologous recombination in an embryonic stem cell. Images PMID:2573070

  12. Hypoxanthine phosphoribosyltransferase from Trypanosoma cruzi as a target for structure-based inhibitor design: crystallization and inhibition studies with purine analogs.

    PubMed Central

    Eakin, A E; Guerra, A; Focia, P J; Torres-Martinez, J; Craig, S P

    1997-01-01

    The hypoxanthine phosphoribosyltransferase (HPRT) from Trypanosoma cruzi is a potential target for enzyme structure-based inhibitor design, based on previous studies which indicate that these parasites lack the metabolic enzymes required for de novo synthesis of purine nucleotides. By using a bacterial complement selection system, 59 purine analogs were assayed for their interaction with the HPRTs from T. cruzi and Homo sapiens. Eight compounds were identified from the bacterial assay to have an affinity for the trypanosomal enzyme. Inhibition constants for four of these compounds against purified recombinant trypanosomal and human HPRTs were determined and compared. The results confirm that the recombinant system can be used to identify compounds which have affinity for the trypanosomal HPRT. Furthermore, the results provide evidence for the importance of chemical modifications at positions 6 and 8 of the purine ring in the binding of these compounds to the HPRTs. An accurate three-dimensional structure of the trypanosomal enzyme will greatly enhance our understanding of the interactions between HPRTs and these compounds. Toward this end, crystallization conditions for the trypanosomal HPRT and preliminary analysis of X-ray diffraction data to a resolution of 2 A is reported. These results represent significant progress toward a structure-based approach to the design of inhibitors of the HPRT of trypanosomes with the long-range goal of developing new drugs for the treatment of Chagas' disease. PMID:9257742

  13. Interaction of the recombinant human methylpurine-DNA glycosylase (MPG protein) with oligodeoxyribonucleotides containing either hypoxanthine or abasic sites.

    PubMed Central

    Miao, F; Bouziane, M; O'Connor, T R

    1998-01-01

    Methylpurine-DNA glycosylases (MPG proteins, 3-methyladenine-DNA glycosylases) excise numerous damaged bases from DNA during the first step of base excision repair. The damaged bases removed by these proteins include those induced by both alkylating agents and/or oxidizing agents. The intrinsic kinetic parameters (k(cat) and K(m)) for the excision of hypoxanthine by the recombinant human MPG protein from a 39 bp oligodeoxyribonucleotide harboring a unique hypoxanthine were determined. Comparison with other reactions catalyzed by the human MPG protein suggests that the differences in specificity are primarily in product release and not binding. Analysis of MPG protein binding to the 39 bp oligodeoxyribonucleotide revealed that the apparent dissociation constant is of the same order of magnitude as the K(m) and that a 1:1 complex is formed. The MPG protein also forms a strong complex with the product of excision, an abasic site, as well as with a reduced abasic site. DNase I footprinting experiments with the MPG protein on an oligodeoxyribonucleotide with a unique hypoxanthine at a defined position indicate that the protein protects 11 bases on the strand with the hypoxanthine and 12 bases on the complementary strand. Competition experiments with different length, double-stranded, hypoxanthine-containing oligodeoxyribonucleotides show that the footprinted region is relatively small. Despite the small footprint, however, oligodeoxyribonucleotides comprising <15 bp with a hypoxanthine have a 10-fold reduced binding capacity compared with hypoxanthine-containing oligodeoxyribonucleotides >20 bp in length. These results provide a basis for other structural studies of the MPG protein with its targets. PMID:9705516

  14. Structural complexes of human adenine phosphoribosyltransferase reveal novel features of the APRT catalytic mechanism.

    PubMed

    Silva, Carlos H T P; Silva, Mario; Iulek, Jorge; Thiemann, Otavio H

    2008-06-01

    Adenine phosphoribosyltransferase (APRT) is an important enzyme component of the purine recycling pathway. Parasitic protozoa of the order Kinetoplastida are unable to synthesize purines de novo and use the salvage pathway for the synthesis of purine bases rendering this biosynthetic pathway an attractive target for antiparasitic drug design. The recombinant human adenine phosphoribosyltransferase (hAPRT) structure was resolved in the presence of AMP in the active site to 1.76 A resolution and with the substrates PRPP and adenine simultaneously bound to the catalytic site to 1.83 A resolution. An additional structure was solved containing one subunit of the dimer in the apo-form to 2.10 A resolution. Comparisons of these three hAPRT structures with other 'type I' PRTases revealed several important features of this class of enzymes. Our data indicate that the flexible loop structure adopts an open conformation before and after binding of both substrates adenine and PRPP. Comparative analyses presented here provide structural evidence to propose the role of Glu104 as the residue that abstracts the proton of adenine N9 atom before its nucleophilic attack on the PRPP anomeric carbon. This work leads to new insights to the understanding of the APRT catalytic mechanism. PMID:18399692

  15. Visfatin impairs endothelium-dependent relaxation in rat and human mesenteric microvessels through nicotinamide phosphoribosyltransferase activity.

    PubMed

    Vallejo, Susana; Romacho, Tania; Angulo, Javier; Villalobos, Laura A; Cercas, Elena; Leivas, Alejandra; Bermejo, Elena; Carraro, Raffaele; Sánchez-Ferrer, Carlos F; Peiró, Concepción

    2011-01-01

    Visfatin, also known as extracellular pre-B-cell colony-enhancing factor (PBEF) and nicotinamide phosphoribosyltransferase (Nampt), is an adipocytokine whose circulating levels are enhanced in metabolic disorders, such as type 2 diabetes mellitus and obesity. Circulating visfatin levels have been positively associated with vascular damage and endothelial dysfunction. Here, we investigated the ability of visfatin to directly impair vascular reactivity in mesenteric microvessels from both male Sprague-Dawley rats and patients undergoing non-urgent, non-septic abdominal surgery. The pre-incubation of rat microvessels with visfatin (50 and 100 ng/mL) did not modify the contractile response to noradrenaline (1 pmol/L to 30 µmol/L), as determined using a small vessel myograph. However, visfatin (10 to 100 ng/mL) concentration-dependently impaired the relaxation to acetylcholine (ACh; 100 pmol/L to 3 µmol/L), without interfering with the endothelium-independent relaxation to sodium nitroprusside (1 nmol/L to 3 µmol/L). In both cultured human umbilical vein endothelial cells and rat microvascular preparations, visfatin (50 ng/mL) stimulated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, as determined by lucigenin-derived chemiluminiscence. The relaxation to ACh impaired by visfatin was restored by the NADPH oxidase inhibitor apocynin (10 µmol/L). Additionally, the Nampt inhibitor APO866 (10 mmol/L to 10 µmol/L), but not an insulin receptor-blocking antibody, also prevented the stimulation of NADPH oxidase and the relaxation impairment elicited by visfatin. Accordingly, the product of Nampt activity nicotinamide mononucleotide (100 nmol/L to 1 mmol/L) stimulated endothelial NADPH oxidase activity and concentration-dependently impaired ACh-induced vasorelaxation. In human mesenteric microvessels pre-contracted with 35 mmol/L potassium chloride, the endothelium-dependent vasodilation to bradykinin (1 nmol/L to 3 µmol/L) was equally impaired by visfatin and restored upon co-incubation with APO866. In conclusion, visfatin impairs endothelium-dependent relaxation through a mechanism involving NADPH oxidase stimulation and relying on Nampt enzymatic activity, and therefore arises as a potential new player in the development of endothelial dysfunction. PMID:22073309

  16. GENETIC ASSAY FOR ANEUPLOIDY: QUANTITATION OF CHROMOSOME LOSS USING A MOUSE/HUMAN MONOCHROMOSOMAL HYBRID CELL LINE (JOURNAL VERSION)

    EPA Science Inventory

    A genetic assay is described in which a mouse/human hybrid cell line R3-5 containing a single human chromosome (a monochromosomal hybrid) is used to detect chemically induced aneuploidy. The hybrid cells are deficient in hypoxanthine guanine phosphoribosyltransferase (HGPRT) and ...

  17. A critical role of nicotinamide phosphoribosyltransferase in human telomerase reverse transcriptase induction by resveratrol in aortic smooth muscle cells

    PubMed Central

    Huang, Peixin; Riordan, Sean M.; Heruth, Daniel P.; Grigoryev, Dmitry N.; Zhang, Li Qin; Ye, Shui Qing

    2015-01-01

    Aging is the predominant risk factor for cardiovascular diseases and contributes to a considerably more severe outcome in patients with acute myocardial infarction. Resveratrol, a polyphenol found in red wine, is a caloric restriction mimetic with potential anti-aging properties which has emerged as a beneficial nutraceutical for patients with cardiovascular disease. Although resveratrol is widely consumed as a nutritional supplement, its mechanism of action remains to be elucidated fully. Here, we report that resveratrol activates human nicotinamide phosphoribosyltransferase (NAMPT), SIRT4 and telomerase reverse transcriptase (hTERT) in human aortic smooth muscle cells. Similar observations were obtained in resveratrol treated C57BL/6J mouse heart and liver tissues. Resverotrol can also augment telomerase activity in both human pulmonary microvascular endothelial cells and A549 cells. Blocking NAMPT and SIRT4 expression prevents induction of hTERT in human aortic smooth muscle cells while overexpression of NAMPT elevates the telomerase activity induced by resveratrol in A549 cells. Together, these results identify a NAMPT-SIRT4-hTERT axis as a novel mechanism by which resveratrol may affect the anti-aging process in human aortic smooth muscle cells, mouse hearts and other cells. These findings enrich our understanding of the positive effects of resveratrol in human cardiovascular diseases. PMID:25926556

  18. A critical role of nicotinamide phosphoribosyltransferase in human telomerase reverse transcriptase induction by resveratrol in aortic smooth muscle cells.

    PubMed

    Huang, Peixin; Riordan, Sean M; Heruth, Daniel P; Grigoryev, Dmitry N; Zhang, Li Qin; Ye, Shui Qing

    2015-05-10

    Aging is the predominant risk factor for cardiovascular diseases and contributes to a considerably more severe outcome in patients with acute myocardial infarction. Resveratrol, a polyphenol found in red wine, is a caloric restriction mimetic with potential anti-aging properties which has emerged as a beneficial nutraceutical for patients with cardiovascular disease. Although resveratrol is widely consumed as a nutritional supplement, its mechanism of action remains to be elucidated fully. Here, we report that resveratrol activates human nicotinamide phosphoribosyltransferase (NAMPT), SIRT4 and telomerase reverse transcriptase (hTERT) in human aortic smooth muscle cells. Similar observations were obtained in resveratrol treated C57BL/6J mouse heart and liver tissues. Resverotrol can also augment telomerase activity in both human pulmonary microvascular endothelial cells and A549 cells. Blocking NAMPT and SIRT4 expression prevents induction of hTERT in human aortic smooth muscle cells while overexpression of NAMPT elevates the telomerase activity induced by resveratrol in A549 cells. Together, these results identify a NAMPT-SIRT4-hTERT axis as a novel mechanism by which resveratrol may affect the anti-aging process in human aortic smooth muscle cells, mouse hearts and other cells. These findings enrich our understanding of the positive effects of resveratrol in human cardiovascular diseases. PMID:25926556

  19. Hypoxanthine-guanine phosophoribosyltransferase (HPRT) deficiency: Lesch-Nyhan syndrome

    Microsoft Academic Search

    Rosa J Torres; Juan G Puig

    2007-01-01

    Deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity is an inborn error of purine metabolism associated with uric acid overproduction and a continuum spectrum of neurological manifestations depending on the degree of the enzymatic deficiency. The prevalence is estimated at 1\\/380,000 live births in Canada, and 1\\/235,000 live births in Spain. Uric acid overproduction is present inall HPRT-deficient patients and is associated

  20. Three-way partial least-squares regression for the simultaneous kinetic-enzymatic determination of xanthine and hypoxanthine in human urine

    Microsoft Academic Search

    José Manuel Amigo; Jordi Coello; Santiago Maspoch

    2005-01-01

    The performance of three-way principal component analysis and three-way partial least-squares regression when applied to a complex kinetic-enzymatic system is studied, in order to investigate the analytical potential of the combined use of these chemometric technologies for non-selective enzymatic systems. A enzymatic-kinetic procedure for the simultaneous determination of hypoxanthine and xanthine in spiked samples of human urine is proposed. The

  1. Nicotinamide phosphoribosyltransferase imparts human endothelial cells with extended replicative lifespan and enhanced angiogenic capacity in a high glucose environment.

    PubMed

    Borradaile, Nica M; Pickering, J Geoffrey

    2009-04-01

    Endothelial dysfunction is a characteristic of aging-related vascular disease and is worsened during diabetes. High glucose can impair endothelial cell (EC) function through cellular accumulation of reactive oxygen species, an insult that can also limit replicative lifespan. Nicotinamide phosphoribosyltransferase (Nampt), also known as PBEF and visfatin, is rate-limiting for NAD+ salvage from nicotinamide and confers resistance to oxidative stress via SIRT1. We therefore sought to determine if Nampt expression could resist the detrimental effects of high glucose and confer a survival advantage to human vascular EC in this pathologic environment. Human aortic EC were infected with retrovirus encoding eGFP or eGFP-Nampt, and FACS-selected to yield populations with similar, modest transgene expression. Using a chronic glucose exposure model we tracked EC populations to senescence, assessed cellular metabolism, and determined in vitro angiogenic function. Overexpression of Nampt increased proliferation and extended replicative lifespan, and did so preferentially during glucose overload. Nampt expression delayed markers of senescence and limited reactive oxygen species accumulation in high glucose through a modest increase in aerobic glycolysis. Furthermore, tube networks formed by Nampt-overexpressing EC were more extensive and glucose-resistant, in accordance with SIRT1-mediated repression of the anti-angiogenic transcription factor, FoxO1. We conclude that Nampt enables proliferating human EC to resist the oxidative stress of aging and of high glucose, and to productively use excess glucose to support replicative longevity and angiogenic activity. Enhancing endothelial Nampt activity may thus be beneficial in scenarios requiring EC-based vascular repair and regeneration during aging and hyperglycemia, such as atherosclerosis and diabetes-related vascular disease. PMID:19302375

  2. Nicotinamide phosphoribosyltransferase (NAMPT/PBEF/visfatin) is constitutively released from human hepatocytes.

    PubMed

    Garten, A; Petzold, S; Barnikol-Oettler, A; Körner, A; Thasler, W E; Kratzsch, J; Kiess, W; Gebhardt, R

    2010-01-01

    Circulating NAMPT (PBEF/visfatin) has pleiotropic functions and is secreted from adipocytes. Since it is doubtful whether serum levels can be explained by secretion from adipocytes alone, we asked whether hepatocytes are also able to liberate NAMPT. Using HepG2 cells and primary rat and human hepatocytes, release of NAMPT into the cell culture supernatant was found to occur constitutively in a time-dependent manner. In primary human hepatocytes, secretion within 24h was far higher than the cellular content, but was neither influenced by inhibitors of secretion nor by glucose, insulin or TNFalpha. As determined by size exclusion chromatography, HepG2 lysates and supernatants primarily contained the dimeric form of NAMPT which exhibited similar in vitro specific enzymatic activity. In primary human hepatocytes, secreted NAMPT was less active. Our results demonstrate that human hepatocytes are a potential source of circulating NAMPT. PMID:19912992

  3. Hypoxanthine, Uric Acid and Allantoin as Indicators of in Vivo Free Radical Reactions. Description of a HPLC Method and Human Brain Microdialysis Data

    Microsoft Academic Search

    N. Marklund; B. Östman; L. Nalmo; L. Persson; L. Hillered

    2000-01-01

    Summary  ¶?A practical one-step high performance liquid chromatography (HPLC) method was developed for the simultaneous determination\\u000a of hypoxanthine, uric acid and allantoin in small (4 ?L) microdialysis samples. The rationale for this work was the current\\u000a interest in hypoxanthine as a marker for energy perturbation in hypoxia\\/ischemia, in uric acid as an endogenous antioxidant,\\u000a and in allantoin as a marker for

  4. Adenine phosphoribosyltransferase deficiency: a previously undescribed genetic defect in man

    PubMed Central

    Kelley, William N.; Levy, Robert I.; Rosenbloom, Frederick M.; Henderson, J. Frank; Seegmiller, J. Edwin

    1968-01-01

    A deficiency of adenine phosphoribosyltransferase (A-PRTase) is described in four members in three generations of one family. A-PRTase is coded by an autosome and the mutants described in this report are heterozygotes for this enzyme defect. The level of enzyme activity in these heterozygotes was inappropriately low, ranging from 21 to 37% of normal rather than the expected 50% of normal. Examination of various physical and chemical properties of the A-PRTase obtained from the mutant heterozygotes failed to reveal differences from the normal enzyme. These patients have no discernable abnormality in uric acid production despite the finding that patients with a deficiency of a closely related enzyme, hypoxanthine-guanine phosphoribosyltransferase, invariably produce excessive quantities of uric acid. A relationship of the A-PRTase deficiency to the disturbance in lipoprotein metabolism observed in the propositus has not been firmly established. Possible manifestations of the homozygous form of this enzyme deficiency will require identification of such individuals in the future. PMID:5676523

  5. Structural and Kinetic Characterization of Quinolinate Phosphoribosyltransferase (hQPRTase) from Homo sapiens

    Microsoft Academic Search

    Huanting Liu; Kerry Woznica; Gemma Catton; Amanda Crawford; Nigel Botting; James H. Naismith

    2007-01-01

    Human quinolinate phosphoribosyltransferase (EC 2.4.2.19) (hQPRTase) is a member of the type II phosphoribosyltransferase family involved in the catabolism of quinolinic acid (QA). It catalyses the formation of nicotinic acid mononucleotide from quinolinic acid, which involves a phosphoribosyl transfer reaction followed by decarboxylation. hQPRTase has been implicated in a number of neurological conditions and in order to study it further,

  6. Alkyl methane sulfonate mutation of diploid human lymphoblasts and Salmonella typhimurium.

    PubMed

    Hoppe, H; Skopeck, T R; Liber, H L; Thilly, W G

    1978-06-01

    Concentration dependence of mutation in equigenerational exposures to methyl, ethyl, propyl, and butyl methanesulfonates has been determined in diploid human lymphoblasts and Salmonella typhimurium. Forward mutation was measured at the hypoxanthine guanine phosphoribosyltransferase locus in human lymphoblasts and at the putative guanine phosphoribosyltransferase locus in S. typhimurium. Reverse mutation at the his G46 locus was also measured in S. typhimurium. This analysis and previous reports support the conclusion that S. typhimurium and mammalian cells are essentially equisensitive to the mutagenic effects of ethyl methanesulfonate when concentration and exposure time are taken into account. Comparison of forward and reverse mutation assays in S. typhimurium reveals no important differences in sensitivities for the four compounds studied. PMID:206353

  7. Anti-oxidant effects of the extracts from the leaves of Chromolaena odorata on human dermal fibroblasts and epidermal keratinocytes against hydrogen peroxide and hypoxanthine-xanthine oxidase induced damage.

    PubMed

    Thang, P T; Patrick, S; Teik, L S; Yung, C S

    2001-06-01

    In cutaneous tissue repair, oxidants and antioxidants play very important roles. In local acute and chronic wounds, oxidants are known to have the ability to cause as cell damage and may function as inhibitory factors to wound healing. The administration of anti-oxidants or free radical scavengers is reportedly helpful, notably in order to limit the delayed sequelae of thermal trauma and to enhance the healing process. Extracts from the leaves of Chromolaena odorata have been shown to be beneficial for treatment of wounds. Studies in vitro of these extracts demonstrated enhanced proliferation of fibroblasts, endothelial cells and keratinocytes, stimulation of keratinocyte migration in an in vitro wound assay, up-regulation of production by keratinocytes of extracellular matrix proteins and basement membrane components, and inhibition of collagen lattice contraction by fibroblasts. In this study, the anti-oxidant effects of both total ethanol and polyphenolic extracts from the plant leaves on hydrogen peroxide and hypoxanthine-xanthine oxidase induced damage to human fibroblasts and keratinocytes were investigated. Cell viability was monitored by a colorimetric assay. The results showed that for fibroblasts, toxicity of hydrogen peroxide or hypoxanthine xanthine oxidase on cells was dose-dependent. Total ethanol extract (TEE) at 400 and 800 microg/ml showed maximum and consistent protective cellular effect on oxidant toxicity at low or high doses of oxidants. The 50 microg/ml concentration of TEE also had significant and slightly protective effects on fibroblasts against hydrogen peroxide and hypoxanthine-xanthine oxidase induced damage, respectively. For keratinocytes, a dose-dependent relationship of oxidant toxicity was only seen with hydrogen peroxide but the protective action of the extract correlated with oxidant dosage. TEE at 400 and 800 microg/ml showed dose-dependent effects with both low and high concentration of oxidants. TEE at 50 microg/ml had no effect on keratinocytes. Pre-treatment with the extracts did not show a protective effect on cells. Polyphenolic extract exhibited a slight anti-oxidant effect. Protection of cells against destruction by inflammatory mediators may be one of the ways in which the extracts from the plant, C. odorata, contribute to wound healing. PMID:11348739

  8. First Crystal Structures of Mycobacterium tuberculosis 6-Oxopurine Phosphoribosyltransferase: Complexes with GMP and Pyrophosphate and with Acyclic Nucleoside Phosphonates Whose Prodrugs Have Antituberculosis Activity.

    PubMed

    Eng, Wai Soon; Hocková, Dana; Špa?ek, Petr; Janeba, Zlatko; West, Nicholas P; Woods, Kyra; Naesens, Lieve M J; Keough, Dianne T; Guddat, Luke W

    2015-06-11

    Human tuberculosis is a chronic infectious disease affecting millions of lives. Because of emerging resistance to current medications, new therapeutic drugs are needed. One potential new target is hypoxanthine-guanine phosphoribosyltransferase (MtHGPRT), a key enzyme of the purine salvage pathway. Here, newly synthesized acyclic nucleoside phosphonates (ANPs) have been shown to be competitive inhibitors of MtHGPRT with Ki values as low as 0.69 ?M. Prodrugs of these compounds arrest the growth of a virulent strain of M. tuberculosis with MIC50 values as low as 4.5 ?M and possess low cytotoxicity in mammalian cells (CC50 values as high as >300 ?M). In addition, the first crystal structures of MtHGPRT (2.03-2.76 Å resolution) have been determined, three of these in complex with novel ANPs and one with GMP and pyrophosphate. These data provide a solid foundation for the further development of ANPs as selective inhibitors of MtHGPRT and as antituberculosis agents. PMID:25915781

  9. Interactions at the Dimer Interface Influence the Relative Efficiencies for Purine Nucleotide Synthesis and Pyrophosphorolysis in a Phosphoribosyltransferase

    SciTech Connect

    Canyuk, Bhutorn; Medrano, Francisco J.; Wenck, MaryAnne; Focia, Pamela J.; Eakin, Ann E.; Craig III, Sydney P. (UNC); (Connecticut)

    2010-03-05

    Enzymes that salvage 6-oxopurines, including hypoxanthine phosphoribosyltransferases (HPRTs), are potential targets for drugs in the treatment of diseases caused by protozoan parasites. For this reason, a number of high-resolution X-ray crystal structures of the HPRTs from protozoa have been reported. Although these structures did not reveal why HPRTs need to form dimers for catalysis, they revealed the existence of potentially relevant interactions involving residues in a loop of amino acid residues adjacent to the dimer interface, but the contributions of these interactions to catalysis remained poorly understood. The loop, referred to as active-site loop I, contains an unusual non-proline cis-peptide and is composed of residues that are structurally analogous with Leu67, Lys68, and Gly69 in the human HPRT. Functional analyses of site-directed mutations (K68D, K68E, K68N, K68P, and K68R) in the HPRT from Trypanosoma cruzi, etiologic agent of Chagas disease, show that the side-chain at position 68 can differentially influence the K{sub m} values for all four substrates as well as the k{sub cat} values for both IMP formation and pyrophosphorolysis. Also, the results for the K68P mutant are inconsistent with a cis-trans peptide isomerization-assisted catalytic mechanism. These data, together with the results of structural studies of the K68R mutant, reveal that the side-chain of residue 68 does not participate directly in reaction chemistry, but it strongly influences the relative efficiencies for IMP formation and pyrophosphorolysis, and the prevalence of lysine at position 68 in the HPRT of the majority of eukaryotes is consistent with there being a biological role for nucleotide pyrophosphorolysis.

  10. Regulation of hypoxanthine transport in Neurospora crassa 

    E-print Network

    Sabina, Richard Lee

    1976-01-01

    the adenine auxotrophic strains, ad-l, ad-8, and the double mutant strain, ad-1;ad-8. Normal (or wild-type) hypoxanthine transport capacity was found in the ad-1 conidia, whereas the ad-8 strain failed to take up any hypoxanthine. The double mutant strains... showed intermediate transport capacities. Similar results were obtained for IMP:pyrophosphorylase activity as- sayed in germinated conidia, The ad-1 strain showed greatest activ- ity, the ad-8 strain showed the least activity, and the double mutant...

  11. Lambda-Chain Production in Human Lymphoblast-Mouse Fibroblast Hybrids

    PubMed Central

    Orkin, Stuart H.; Buchanan, Philip D.; Yount, William J.; Reisner, Howard; Littlefield, John W.

    1973-01-01

    Mutant human lymphoblast cells deficient in hypoxanthine phosphoribosyltransferase (EC 2.4.2.8) activity were hybridized with thymidine kinase (EC 2.7.1.21)-deficient mouse fibroblasts. Hybrid cells were readily selected, as both parental lines were nonreverting and eliminated by hypoxanthine-amethopterinthymidine medium. Human lambda (?) chain was the only immunoglobulin chain produced by the lymphoblast parent, as determined by immunofluorescent techniques. Two independent hybrid clones chosen for detailed study synthesized human ? chain, and continued to do so after prolonged culture. As in both parental lines, no human immunoglobulin heavy chains, complements C3 or C4, or ?1-antitrypsin, or mouse immunoglobulin chains or complement C5 were detectable in the hybrids. Selection against thymidine kinase-containing hybrid cells with 5-bromodeoxyuridine did not eliminate positive ?-chain reactivity, suggesting that the kinase and ?-chain loci are not linked. The continued production of an immunoglobulin chain by human lymphoblast-mouse fibroblast hybrids contrasts with the extinction of other differentiated functions in several hybrid systems, and indicates that gene localization and linkage analysis for human immunoglobulin chains should be feasible with this system. Images PMID:4599625

  12. The synthetic substance hypoxanthine 3-N-oxide elicits alarm reactions in zebrafish (Danio rerio)

    PubMed Central

    Parra, Kevin V.; Adrian, James C.; Gerlai, Robert

    2009-01-01

    Zebrafish, one of the preferred study species of geneticists, is gaining increasing popularity in behavioral neuroscience. This small and prolific species may be an excellent tool with which the biological mechanisms of vertebrate brain function and behavior are investigated. Zebrafish has been proposed as a model organism in the analysis of fear responses and human anxiety disorders. Species-specific cues signaling the presence of predators have been successfully utilized in such research. Zebrafish has been shown to respond to its natural alarm substance with species-typical fear reactions. However, the extraction of this alarm substance and ascertaining its consistent dosing has been problematic. A synthetic substance with a known chemical identity and molecular weight would allow precise dosing and experimental control. Previously, the chemical component, hypoxanthine 3-N-oxide, common to several fish alarm substances has been identified and has been shown to elicit alarm reactions in fish species belonging to the Osteriophysan superorder. In the current study we investigate the effect of hypoxanthine 3-N-oxide by exposing zebrafish to three different concentrations of this synthetic substance. Our results show that the substance efficaciously induces species-typical fear reactions increasing the number of erratic movement episodes and jumps in zebrafish. We discuss the translational relevance of our findings and conclude that hypoxanthine 3-N-oxide will have utility to elicit fear responses in the laboratory in a precisely controlled manner in zebrafish. PMID:19583985

  13. V(D)J RECOMBINASE-MEDIATED DELETION OF THE HPRT GENE IN T-LYMPHOCYTES FROM ADULT HUMANS

    EPA Science Inventory

    The hprt T-cell cloning assay allows the detection of mutations occurring in vivo in the hypoxanthine guanine phosphoribosyltransferase (hprt) gene of T-lymphocytes. e have shown previously that the illegitimate activity of V(D)J recombinase accounts for about 40% of the hprt mut...

  14. Structural and kinetic characterization of quinolinate phosphoribosyltransferase (hQPRTase) from homo sapiens.

    PubMed

    Liu, Huanting; Woznica, Kerry; Catton, Gemma; Crawford, Amanda; Botting, Nigel; Naismith, James H

    2007-10-26

    Human quinolinate phosphoribosyltransferase (EC 2.4.2.19) (hQPRTase) is a member of the type II phosphoribosyltransferase family involved in the catabolism of quinolinic acid (QA). It catalyses the formation of nicotinic acid mononucleotide from quinolinic acid, which involves a phosphoribosyl transfer reaction followed by decarboxylation. hQPRTase has been implicated in a number of neurological conditions and in order to study it further, we have carried out structural and kinetic studies on recombinant hQPRTase. The structure of the fully active enzyme overexpressed in Escherichia coli was solved using multiwavelength methods to a resolution of 2.0 A. hQPRTase has a alpha/beta barrel fold sharing a similar overall structure with the bacterial QPRTases. The active site of hQPRTase is located at an alpha/beta open sandwich structure that serves as a cup for the alpha/beta barrel of the adjacent subunit with a QA binding site consisting of three arginine residues (R102, R138 and R161) and two lysine residues (K139 and K171). Mutation of these residues affected substrate binding or abolished the enzymatic activity. The kinetics of the human enzyme are different to the bacterial enzymes studied, hQPRTase is inhibited competitively and non-competitively by one of its substrates, 5-phosphoribosylpyrophosphate (PRPP). The human enzyme adopts a hexameric arrangement, which places the active sites in close proximity to each other. PMID:17868694

  15. STRUCTURAL AND KINETIC CHARACTERIZATION OF QUINOLINATE PHOSPHORIBOSYLTRANSFERASE (hQPRTase) FROM HOMO SAPIENS

    PubMed Central

    Liu, Huanting; Woznica, Kerry; Catton, Gemma; Crawford, Amanda; Botting, Nigel; Naismith, James H.

    2012-01-01

    Human quinolinate phosphoribosyltransferase (EC 2.4.2.19) (hQPRTase) is a member of the type II phosphoribosyltransferase family involved in the catabolism of quinolinic acid. It catalyses the formation of nicotinic acid mononucleotide from quinolinic acid, which involves a phosphoribosyl transfer reaction followed by decarboxylation. hQPRTase has been implicated in a number of neurological conditions and in order to study it further, we have carried out structural and kinetic studies on recombinant hQPRTase. The structure of the fully active enzyme overexpressed in E. coli was solved using multiwavelength methods to a resolution of 2.0 Å. hQPRTase has a ?/? barrel fold sharing a similar overall structure with the bacterial QPRTases. The active site of hQPRTase is located at an ?/? open sandwich structure that serves as a cup for the ?/? barrel of the adjacent subunit with a QA binding site consisting of three arginine residues (R102, R138 and R161) and two lysine residues (K139 and R171). Mutation of these residues affected substrate binding or abolished the enzymatic activity. The kinetics of the human enzyme are different to the bacterial enzymes studied, hQPRTase is inhibited competitively and non-competitively by one of its substrates, PRPP. The human enzyme adopts a hexameric arrangement which places the active sites in close proximity to each other. PMID:17868694

  16. The kinetics of hypoxanthine efflux from the rat brain

    Microsoft Academic Search

    Zoran B. Redzic; Aleksandra Isakovic; Malcolm B. Segal; Sarah A. Thomas; Ljubisa M. Rakic

    2001-01-01

    The brain efflux of radiolabelled hypoxanthine in the rat was rapid in the first minute after injection [Keff(i)=0.21±0.06 min?1], which was saturable with a Vmax=13.08±0.81 nM min?1 g?1, and a high Km,app (67.2±13.4 ?M); the Ki,app for inosine was 31.5±7.6 ?M. Capillary depletion analysis indicated that hypoxanthine accumulates in neurons and glia with the time. From cross-inhibition studies with different

  17. The kinetics of hypoxanthine efflux from the rat brain.

    PubMed

    Redzic, Z B; Isakovic, A; Segal, M B; Thomas, S A; Rakic, L M

    2001-04-27

    The brain efflux of radiolabelled hypoxanthine in the rat was rapid in the first minute after injection [K(eff)(i)=0.21+/-0.06 min(-1)], which was saturable with a V(max)=13.08+/-0.81 nM min(-1) g(-1), and a high K(m,app) (67.2+/-13.4 microM); the K(i,app) for inosine was 31.5+/-7.6 microM. Capillary depletion analysis indicated that hypoxanthine accumulates in neurons and glia with the time. From cross-inhibition studies with different purines and pyrimidines, it suggests that these molecules could also be important substrates for this carrier. PMID:11311886

  18. The function of nicotinamide phosphoribosyltransferase in the heart.

    PubMed

    Hsu, Chiao-Po; Yamamoto, Takanobu; Oka, Shinichi; Sadoshima, Junichi

    2014-11-01

    In addition to its roles as a coenzyme and an electron transfer molecule, nicotinamide adenine dinucleotide (NAD+) has emerged as a substrate of sirtuins, a family of enzymes that control aging and metabolism. Nicotinamide phosphoribosyltransferase (Nampt), a rate-limiting enzyme in the NAD+ salvage pathway, plays an important role in controlling the level of NAD+ and the activity of Sirt1 in the heart and the cardiomyocytes therein. Nampt protects the heart from ischemia and reperfusion injury by stimulating Sirt1. In this review, we summarize what is currently known regarding the function of Nampt in the heart. PMID:25277684

  19. Isolation of the human chromosomal band Xq28 within somatic cell hybrids by fragile X site breakage

    SciTech Connect

    Warren, S.T.; Knight, S.J.L.; Peters, J.F.; Stayton, C.L.; Consalez, G.G.; Zhang, F. (Emory Univ. School of Medicine, Atlanta, GA (USA))

    1990-05-01

    The chromosomal fragile-site mapping to Xq27.3 is associated with a frequent form of mental retardation and is prone to breakage after induced deoxyribonucleotide pool perturbation. The human hypoxanthine phosphoribosyltransferase (HPRT) and glucose-6-phosphate dehydrogenase (G6PD) genes flank the fragile X chromosome site and can be used to monitor integrity of the site in human-hamster somatic cell hybrids deficient in the rodent forms of these activities. After induction of the fragile X site, negative selection for HPRT and positive enrichment for G6PD resulted in 31 independent colonies of HPRT{sup {minus}}, G6PD{sup +} phenotype. Southern blot analysis demonstrated the loss of all tested markers proximal to the fragile X site with retention of all tested human Xq28 loci in a majority of the hybrids. In situ hybridization with a human-specific probe demonstrated the translocation of a small amount of human DNA to rodent chromosomes in these hybrids, suggesting chromosome breakage at the fragile X site and the subsequent translocation of Xq28. Southern blot hybridization of hybrid-cell DNA, resolved by pulsed-field gel electrophoresis, for human-specific repetitive sequences revealed abundant CpG-islands within Xq28, consistent with its known gene density. The electrophoretic banding patterns of human DNA among the hybrids were remarkably consistent, suggesting that fragile X site breakage is limited to a relatively small region in Xq27-28.

  20. The kinetics of hypoxanthine transport across the perfused choroid plexus of the sheep

    Microsoft Academic Search

    Zoran B Redzic; Jovana M Gasic; Malcolm B Segal; Ivanka D Markovic; Aleksandra J Isakovic; Miodrag Lj Rakic; Sarah A Thomas; Ljubisa M Rakic

    2002-01-01

    The uptake of principal salvageable nucleobase hypoxanthine was investigated across the basolateral membrane of the sheep choroid plexus (CP) perfused in situ. The results suggest that hypoxanthine uptake was Na+-independent, which means that transport system on the basolateral membrane can mediate the transport in both directions. Although the unlabelled nucleosides adenosine and inosine markedly reduce the transport it seems that

  1. Purine and pyrimidine metabolism in human gliomas: relation to chromosomal aberrations.

    PubMed

    Bardot, V; Dutrillaux, A M; Delattre, J Y; Vega, F; Poisson, M; Dutrillaux, B; Luccioni, C

    1994-08-01

    Chromosomal aberrations in human gliomas are principally numerical. In tumours of low malignancy, karyotypes are frequently normal, but occasionally an excess of chromosome 7 and a loss of sex chromosome are observed. In highly malignant tumours, the most frequent aberrations are gain of chromosome 7, loss of chromosome 10 and less frequently losses or deletions of chromosomes 9, 22, 6, 13 and 14 or gains of chromosomes 19 and 20. To understand the meaning of these chromosome imbalances, the relationships between chromosome abnormalities and metabolic disturbances were studied. The losses or deletions observed affected principally chromosomes carrying genes encoding enzymes involved in purine metabolism. The activities of ten enzymes were measured: adenosine kinase, adenine phosphoribosyltransferase, adenylate kinase, methylthioadenosine phosphorylase, hypoxanthine phosphoribosyltransferase, adenylosuccinate lyase, inosine monophosphate dehydrogenase, adenosine deaminase, nucleoside phosphorylase and adenosine monophosphate deaminase. In parallel, two enzymes involved in pyrimidine metabolism, thymidine kinase and thymidylate synthase (TS), were studied. The activities of all these enzymes were measured on samples from 30 human primary glial tumours with low or high malignancy, six xenografted tumours at different passages, four portions of normal brain tissue and four non-glial brain neoplasms. As suggested by cytogenetic data, the enzymatic results showed a relatively low activity of purine metabolism in glial tumours when compared with normal brain and non-glial brain neoplasms. Considering the two enzymes involved in pyrimidine metabolism, only TS had higher activity in glial tumours of high malignancy than in normal brain. In comparison with normal brain, the balance between salvage and de novo pathways changes in gliomas, and even more in grafted tumours, in favour of de novo synthesis. The relation between chromosomes and metabolic imbalances does not correspond to a simple gene dosage effect in these tumours. These data suggest that the decrease of adenosine metabolism occurs before chromosomal aberrations appear, since it is observed in tumours of low malignancy when most karyotypes are still normal, and that the de novo pathway increases with tumour progression. PMID:8054268

  2. Proinflammatory actions of visfatin/nicotinamide phosphoribosyltransferase (Nampt) involve regulation of insulin signaling pathway and Nampt enzymatic activity.

    PubMed

    Jacques, Claire; Holzenberger, Martin; Mladenovic, Zvezdana; Salvat, Colette; Pecchi, Emilie; Berenbaum, Francis; Gosset, Marjolaine

    2012-04-27

    Visfatin (also termed pre-B-cell colony-enhancing factor (PBEF) or nicotinamide phosphoribosyltransferase (Nampt)) is a pleiotropic mediator acting on many inflammatory processes including osteoarthritis. Visfatin exhibits both an intracellular enzymatic activity (nicotinamide phosphoribosyltransferase, Nampt) leading to NAD synthesis and a cytokine function via the binding to its hypothetical receptor. We recently reported the role of visfatin in prostaglandin E(2) (PGE(2)) synthesis in chondrocytes. Here, our aim was to characterize the signaling pathways involved in this response in exploring both the insulin receptor (IR) signaling pathway and Nampt activity. IR was expressed in human and murine chondrocytes, and visfatin triggered Akt phosphorylation in murine chondrocytes. Blocking IR expression with siRNA or activity using the hydroxy-2-naphthalenyl methyl phosphonic acid tris acetoxymethyl ester (HNMPA-(AM)(3)) inhibitor diminished visfatin-induced PGE(2) release in chondrocytes. Moreover, visfatin-induced IGF-1R(-/-) chondrocytes released higher concentration of PGE(2) than IGF-1R(+/+) cells, a finding confirmed with an antibody that blocked IGF-1R. Using RT-PCR, we found that visfatin did not regulate IR expression and that an increased insulin release was also unlikely to be involved because insulin was unable to increase PGE(2) release. Inhibition of Nampt activity using the APO866 inhibitor gradually decreased PGE(2) release, whereas the addition of exogenous nicotinamide increased it. We conclude that the proinflammatory actions of visfatin in chondrocytes involve regulation of IR signaling pathways, possibly through the control of Nampt enzymatic activity. PMID:22399297

  3. Defects in purine nucleotide metabolism lead to substantial incorporation of xanthine and hypoxanthine into DNA and RNA

    PubMed Central

    Pang, Bo; McFaline, Jose L.; Burgis, Nicholas E.; Dong, Min; Taghizadeh, Koli; Sullivan, Matthew R.; Elmquist, C. Eric; Cunningham, Richard P.; Dedon, Peter C.

    2012-01-01

    Deamination of nucleobases in DNA and RNA results in the formation of xanthine (X), hypoxanthine (I), oxanine, and uracil, all of which are miscoding and mutagenic in DNA and can interfere with RNA editing and function. Among many forms of nucleic acid damage, deamination arises from several unrelated mechanisms, including hydrolysis, nitrosative chemistry, and deaminase enzymes. Here we present a fourth mechanism contributing to the burden of nucleobase deamination: incorporation of hypoxanthine and xanthine into DNA and RNA caused by defects in purine nucleotide metabolism. Using Escherichia coli and Saccharomyces cerevisiae with defined mutations in purine metabolism in conjunction with analytical methods for quantifying deaminated nucleobases in DNA and RNA, we observed large increases (up to 600-fold) in hypoxanthine in both DNA and RNA in cells unable to convert IMP to XMP or AMP (IMP dehydrogenase, guaB; adenylosuccinate synthetase, purA, and ADE12), and unable to remove dITP/ITP and dXTP/XTP from the nucleotide pool (dITP/XTP pyrophosphohydrolase, rdgB and HAM1). Conversely, modest changes in xanthine levels were observed in RNA (but not DNA) from E. coli lacking purA and rdgB and the enzyme converting XMP to GMP (GMP synthetase, guaA). These observations suggest that disturbances in purine metabolism caused by known genetic polymorphisms could increase the burden of mutagenic deaminated nucleobases in DNA and interfere with gene expression and RNA function, a situation possibly exacerbated by the nitrosative stress of concurrent inflammation. The results also suggest a mechanistic basis for the pathophysiology of human inborn errors of purine nucleotide metabolism. PMID:22308425

  4. Discovery and characterization of novel small-molecule inhibitors targeting nicotinamide phosphoribosyltransferase.

    PubMed

    Xu, Tian-Ying; Zhang, Sai-Long; Dong, Guo-Qiang; Liu, Xin-Zhu; Wang, Xia; Lv, Xiao-Qun; Qian, Qi-Jun; Zhang, Ruo-Yu; Sheng, Chun-Quan; Miao, Chao-Yu

    2015-01-01

    Nicotinamide phosphoribosyltransferase (NAMPT) is a promising anticancer target. Using high throughput screening system targeting NAMPT, we obtained a potent NAMPT inhibitor MS0 (China Patent ZL201110447488.9) with excellent in vitro activity (IC50?=?9.87?±?1.15nM) and anti-proliferative activity against multiple human cancer cell lines including stem-like cancer cells. Structure-activity relationship studies yielded several highly effective analogues. These inhibitors specifically bound NAMPT, rather than downstream NMNAT. We provided the first chemical case using cellular thermal shift assay to explain the difference between in vitro and cellular activity; MS7 showed best in vitro activity (IC50?=?0.93?±?0.29?nM) but worst cellular activity due to poor target engagement in living cells. Site-directed mutagenesis studies identified important residues for NAMPT catalytic activity and inhibitor binding. The present findings contribute to deep understanding the action mode of NAMPT inhibitors and future development of NAMPT inhibitors as anticancer agents. PMID:26040985

  5. Prognostic value of serum nicotinamide phosphoribosyltransferase in patients with bladder cancer

    PubMed Central

    Zhang, Kui; Zhou, Bin; Zhang, Peng; Zhang, Zhu; Chen, Peng; Pu, Yan; Song, Yaping; Zhang, Lin

    2014-01-01

    Aim To analyze the serum nicotinamide phosphoribosyltransferase (Nampt) level and its prognostic value in bladder cancer (BC). Methods The study included 131 patients with transitional cell BC and 109 healthy controls from the West China Hospital of Sichuan University in the period between 2007 and 2013. Nampt concentration in serum was measured by commercial ELISA kits for human Nampt. Results The serum Nampt protein level in patients with BC (mean?±?standard deviation, 16.02?±?7.95 ng/mL) was significantly higher than in the control group (6.46?±?2.08 ng/mL) (P?14.74 ng/mL) indicating shorter recurrence-free survival rate (hazard ratio?=?2.85, 95% confidence interval, 1.01-8.06; P?=?0.048). Conclusion Our results suggest that serum Nampt level may serve as a biomarker of BC and an independent prognostic marker of non-muscle-invasive BC. PMID:25358883

  6. Molecular characterization of quinolinate phosphoribosyltransferase (QPRtase) in Nicotiana.

    PubMed

    Sinclair, S J; Murphy, K J; Birch, C D; Hamill, J D

    2000-11-01

    Quinolate acid phosphoribosyltransferase (QPRTase), a key enzyme in nicotinamide adenine dinucleotide (NAD) biosynthesis, also plays an important role in ensuring nicotinic acid is available for the synthesis of defensive pyridine alkaloids in Nicotiana species. In this study, cDNAs for QPRTase were characterized from N. rustica and N. tabacum. Deduced proteins from both cDNAs are almost identical and contain a 24 amino acid N-terminal extension, not reported in other QPRTases, that has characteristics of a mitochondrial targeting sequence. In N. tabacum and N. sylvestris, both of which contain nicotine as the major pyridine alkaloid, QPRTase transcript was detected in roots, the site of nicotine synthesis, but not in leaves. QPRTase transcript levels increased markedly in roots of both species 12-24 h after damage to aerial tissues, with a concomitant rise in transcript levels of putrescine N-methyltransferase (PMT), another key enzyme in nicotine biosynthesis. In N. glauca, however, in which anabasine represents the major pyridine alkaloid, QPRTase transcript was detected in both leaf and root tissues. Moreover, wound induction of QPRTase but not PMT was observed in leaf tissues, and not in roots, 12-24 h after wounding. Southern analysis of genomic DNA from the Nicotiana species noted above, and also several others from within the genus, suggested that QPRTase is encoded by a small gene family in all the species investigated. PMID:11198422

  7. Quantification and molecular characterization of hprt mutants of human T-lymphocytes.

    PubMed Central

    Moore, M M; Harrington-Brock, K; Zimmerman, L J; Burnette, L P; Smith, T W; Everson, R B; O'Neill, J P; Fuscoe, J C

    1993-01-01

    Somatic mutations have been implicated as critical early events in carcinogenesis. Point mutations, deletions, and translocation events have been shown to activate oncogenes or inactivate suppressor oncogenes. In human population monitoring, quantitative analysis of mutation events that affect gene function is limited to those genes whose cellular phenotypes can be identified by selection procedures and to those tissues (like blood) that are accessible for analysis. In an effort to determine the frequency and types of mutations that can be detected at the hypoxanthine guanine phosphoribosyltransferase (hprt) gene, we have used the T-cell cloning assay and have developed a strategy to propagate mutants and screen for point mutations and breakage events. Early in the clonal expansion of mutants, 1-2 x 10(4) cells are prepared as a crude cell lysate, and a sample is analyzed using the multiplex polymerase chain reaction (PCR). Those mutants that yield altered DNA fragments are then expanded for Southern blot hybridization, PCR, flanking probe isolation, and DNA sequencing. To date we have found presumed point mutations, intragenic deletions, and deletions that extend outside of the hprt gene. By analyzing mutations in selectable, nonessential gene markers, it should be possible to understand mechanisms of both spontaneous and induced genetic damage. An association of these specific genetic events with human diseases and the evaluation of the ability of environmental chemicals to induce these specific types of mutations will lead to a rational basis for evaluating risks from various chemical exposures. Images FIGURE 3. PMID:8143621

  8. The kinetics of hypoxanthine transport across the perfused choroid plexus of the sheep.

    PubMed

    Redzic, Zoran B; Gasic, Jovana M; Segal, Malcolm B; Markovic, Ivanka D; Isakovic, Aleksandra J; Rakic, Miodrag Lj; Thomas, Sarah A; Rakic, Ljubisa M

    2002-01-25

    The uptake of principal salvageable nucleobase hypoxanthine was investigated across the basolateral membrane of the sheep choroid plexus (CP) perfused in situ. The results suggest that hypoxanthine uptake was Na+-independent, which means that transport system on the basolateral membrane can mediate the transport in both directions. Although the unlabelled nucleosides adenosine and inosine markedly reduce the transport it seems that this inhibition was due to nucleoside degradation into nucleobases in the cells, since non-metabolised nucleoside analogue NBTI did not inhibit the transport. The presence of adenine also inhibits hypoxanthine uptake while the addition of the pyrimidines does not show any effect, so it seems that the transport of purine nucleobases through basolateral membrane is mediated via a common transporter which is different from the nucleoside transporters. The inclusion of allopurinol in the perfusion fluid did not change the value and general shape of the curve for the uptake which suggest that degradation of hypoxanthine into xanthine and uric acid does not occur in the CP. The capacity of the CP basolateral membrane to transport hypoxanthine is high (90.63+/-3.79 nM/min/g) and close to the values obtained for some essential amino acids by the CP and blood-brain barrier, while the free diffusion is negligible. The derived value of Km (20.72+/-2.42 microM) is higher than the concentration of hypoxanthine in the sheep plasma (15.61+/-2.28 microM) but less than a half of the concentration in the CSF, which indicates that the transport system at basolateral membrane mostly mediates the efflux of hypoxanthine from the cerebrospinal fluid in vivo. PMID:11792365

  9. Orotate phosphoribosyltransferase from Corynebacterium ammoniagenes lacking a conserved lysine.

    PubMed

    Wang, Xing; Ma, Cuiqing; Wang, Xiuwen; Xu, Ping

    2007-12-01

    The pyrE gene, encoding orotate phosphoribosyltransferase (OPRTase), was cloned by nested PCR and colony blotting from Corynebacterium ammoniagenes ATCC 6872, which is widely used in nucleotide production. Sequence analysis shows that there is a lack of an important conserved lysine (Lys 73 in Salmonella enterica serovar Typhimurium OPRTase) in the C. ammoniagenes OPRTase. This lysine has been considered to contribute to the initiation of catalysis. The enzyme was overexpressed and purified from a recombinant Escherichia coli strain. The molecular mass of the purified OPRTase was determined to be 45.4 +/- 1.5 kDa by gel filtration. Since the molecular mass for the subunit of the enzyme was 21.3 +/- 0.6 kDa, the native enzyme exists as a dimer. Divalent magnesium was necessary for the activity of the enzyme and can be substituted for by Mn2+ and Co2+. The optimal pH for the forward (phosphoribosyl transfer) reaction is 10.5 to 11.5, which is higher than that of other reported OPRTases, and the optimal pH for the reverse (pyrophosphorolysis) reaction is 5.5 to 6.5. The Km values for the four substrates were determined to be 33 microM for orotate, 64 microM for 5-phosphoribosyl-1-pyrophosphate (PRPP), 45 microM for orotidine-5-phosphate (OMP), and 36 microM for pyrophosphate. The Km value for OMP is much larger than those of other organisms. These differences may be due to the absence of Lys 73, which is present in the active sites of other OPRTases and is known to interact with OMP and PRPP. PMID:17921291

  10. Dissociative electron attachment to the gas-phase nucleobase hypoxanthine

    NASA Astrophysics Data System (ADS)

    Dawley, M. Michele; Tanzer, Katrin; Carmichael, Ian; Denifl, Stephan; Ptasi?ska, Sylwia

    2015-06-01

    We present high-resolution measurements of the dissociative electron attachment (DEA) to isolated gas-phase hypoxanthine (C5H4N4O, Hyp), a tRNA purine base. The anion mass spectra and individual ion efficiency curves from Hyp were measured as a function of electron energy below 9 eV. The mass spectra at 1 and 6 eV exhibit the highest anion yields, indicating possible common precursor ions that decay into the detectable anionic fragments. The (Hyp - H) anion (C5H3N4O-) exhibits a sharp resonant peak at 1 eV, which we tentatively assign to a dipole-bound state of the keto-N1H,N9H tautomer in which dehydrogenation occurs at either the N1 or N9 position based upon our quantum chemical computations (B3LYP/6-311+G(d,p) and U(MP2-aug-cc-pVDZ+)) and prior studies with adenine. This closed-shell dehydrogenated anion is the dominant fragment formed upon electron attachment, as with other nucleobases. Seven other anions were also observed including (Hyp - NH)-, C4H3N4-/C4HN3O-, C4H2N3-, C3NO-/HC(HCN)CN-, OCN-, CN-, and O-. Most of these anions exhibit broad but weak resonances between 4 and 8 eV similar to many analogous anions from adenine. The DEA to Hyp involves significant fragmentation, which is relevant to understanding radiation damage of biomolecules.

  11. Dissociative electron attachment to the gas-phase nucleobase hypoxanthine.

    PubMed

    Dawley, M Michele; Tanzer, Katrin; Carmichael, Ian; Denifl, Stephan; Ptasi?ska, Sylwia

    2015-06-01

    We present high-resolution measurements of the dissociative electron attachment (DEA) to isolated gas-phase hypoxanthine (C5H4N4O, Hyp), a tRNA purine base. The anion mass spectra and individual ion efficiency curves from Hyp were measured as a function of electron energy below 9 eV. The mass spectra at 1 and 6 eV exhibit the highest anion yields, indicating possible common precursor ions that decay into the detectable anionic fragments. The (Hyp - H) anion (C5H3N4O(-)) exhibits a sharp resonant peak at 1 eV, which we tentatively assign to a dipole-bound state of the keto-N1H,N9H tautomer in which dehydrogenation occurs at either the N1 or N9 position based upon our quantum chemical computations (B3LYP/6-311+G(d,p) and U(MP2-aug-cc-pVDZ+)) and prior studies with adenine. This closed-shell dehydrogenated anion is the dominant fragment formed upon electron attachment, as with other nucleobases. Seven other anions were also observed including (Hyp - NH)(-), C4H3N4 (-)/C4HN3O(-), C4H2N3 (-), C3NO(-)/HC(HCN)CN(-), OCN(-), CN(-), and O(-). Most of these anions exhibit broad but weak resonances between 4 and 8 eV similar to many analogous anions from adenine. The DEA to Hyp involves significant fragmentation, which is relevant to understanding radiation damage of biomolecules. PMID:26049525

  12. Reduced urinary serotonin excretion after intake of high doses of hypoxanthine.

    PubMed

    Manzke, H; Gustmann, H

    1989-01-01

    Two healthy volunteers were treated with hypoxanthine 3 x 1 g and allopurinol 3 x 100 mg daily for 1 week. During this treatment serum oxypurine concentration and urinary oxypurine excretion increased as expected. No side effects were observed except for some mild daytime drowsiness and lethargy. Measurements of urinary serotonin (5-HT) excretion showed decreases to as much as 60% below initial values. Decreased urinary 5-HT excretion was also found in a patient with incomplete Lesch-Nyhan syndrome during treatment with high doses of hypoxanthine. His neurological symptoms improved slightly. The results suggest that high doses of hypoxanthine exert a nonspecific sedative effect on both patients with Lesch-Nyhan syndrome and healthy controls. The cause is probably a reduced synthesis or release of 5-HT. PMID:2707279

  13. Validation of adequate endogenous reference genes for the normalisation of qPCR gene expression data in human post mortem tissue.

    PubMed

    Koppelkamm, Antje; Vennemann, Benedikt; Fracasso, Tony; Lutz-Bonengel, Sabine; Schmidt, Ulrike; Heinrich, Marielle

    2010-09-01

    Gene expression analyses based on messenger RNA (mRNA) profiling require accurate data normalisation. When using endogenous reference genes, these have to be validated carefully. Therefore, we examined the transcript stability of 10 potential reference genes using quantitative real-time polymerase chain reaction: beta actin, 18S rRNA, glyceraldehyde-3-phosphate dehydrogenase, TATA box-binding protein, hypoxanthine phosphoribosyl-transferase I, beta-2-microglobulin, hydroxymethylbilane synthase, succinate dehydrogenase complex, subunit A, cyclophilin A and ubiquitin C. The aim of the current study was to assess which reference genes show stable mRNA levels in human post mortem cardiac muscle, skeletal muscle and brain tissue. Considering cardiac muscle tissue, CYCA and TBP were identified as the most stable while in skeletal muscle tissue, SDHA and TBP, and in brain tissue, SDHA and HMBS turned out to be the most stable. Furthermore, we recommend a minimum of four carefully validated endogenous control genes for reliable data normalisation in human post mortem tissue. Parameters influencing the stability of transcript amounts were found to be mainly the post mortem interval in cardiac muscle and skeletal muscle tissue and the donor's cause of death in skeletal muscle and brain samples. Further parameters like gender, age at death and body mass index were found to influence mRNA quantities in skeletal muscle only. The set of stable control genes identified in this study may be used in further studies if the composition of the samples is similar to the one used here. PMID:20300940

  14. Thirdhand smoke causes DNA damage in human cells

    PubMed Central

    Hang, Bo

    2013-01-01

    Exposure to thirdhand smoke (THS) is a newly described health risk. Evidence supports its widespread presence in indoor environments. However, its genotoxic potential, a critical aspect in risk assessment, is virtually untested. An important characteristic of THS is its ability to undergo chemical transformations during aging periods, as demonstrated in a recent study showing that sorbed nicotine reacts with the indoor pollutant nitrous acid (HONO) to form tobacco-specific nitrosamines (TSNAs) such as 4-(methylnitrosamino)-4-(3-pyridyl)butanal (NNA) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The goal of this study was to assess the genotoxicity of THS in human cell lines using two in vitro assays. THS was generated in laboratory systems that simulated short (acute)- and long (chronic)-term exposures. Analysis by liquid chromatography–tandem mass spectrometry quantified TSNAs and common tobacco alkaloids in extracts of THS that had sorbed onto cellulose substrates. Exposure of human HepG2 cells to either acute or chronic THS for 24h resulted in significant increases in DNA strand breaks in the alkaline Comet assay. Cell cultures exposed to NNA alone showed significantly higher levels of DNA damage in the same assay. NNA is absent in freshly emitted secondhand smoke, but it is the main TSNA formed in THS when nicotine reacts with HONO long after smoking takes place. The long amplicon–quantitative PCR assay quantified significantly higher levels of oxidative DNA damage in hypoxanthine phosphoribosyltransferase 1 (HPRT) and polymerase ? (POLB) genes of cultured human cells exposed to chronic THS for 24h compared with untreated cells, suggesting that THS exposure is related to increased oxidative stress and could be an important contributing factor in THS-mediated toxicity. The findings of this study demonstrate for the first time that exposure to THS is genotoxic in human cell lines. PMID:23462851

  15. The Small Molecule GMX1778 Is a Potent Inhibitor of NAD+ Biosynthesis: Strategy for Enhanced Therapy in Nicotinic Acid Phosphoribosyltransferase 1-Deficient Tumors?

    PubMed Central

    Watson, Mark; Roulston, Anne; Bélec, Laurent; Billot, Xavier; Marcellus, Richard; Bédard, Dominique; Bernier, Cynthia; Branchaud, Stéphane; Chan, Helen; Dairi, Kenza; Gilbert, Karine; Goulet, Daniel; Gratton, Michel-Olivier; Isakau, Henady; Jang, Anne; Khadir, Abdelkrim; Koch, Elizabeth; Lavoie, Manon; Lawless, Michael; Nguyen, Mai; Paquette, Denis; Turcotte, Émilie; Berger, Alvin; Mitchell, Matthew; Shore, Gordon C.; Beauparlant, Pierre

    2009-01-01

    GMX1777 is a prodrug of the small molecule GMX1778, currently in phase I clinical trials for the treatment of cancer. We describe findings indicating that GMX1778 is a potent and specific inhibitor of the NAD+ biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT). Cancer cells have a very high rate of NAD+ turnover, which makes NAD+ modulation an attractive target for anticancer therapy. Selective inhibition by GMX1778 of NAMPT blocks the production of NAD+ and results in tumor cell death. Furthermore, GMX1778 is phosphoribosylated by NAMPT, which increases its cellular retention. The cytotoxicity of GMX1778 can be bypassed with exogenous nicotinic acid (NA), which permits NAD+ repletion via NA phosphoribosyltransferase 1 (NAPRT1). The cytotoxicity of GMX1778 in cells with NAPRT1 deficiency, however, cannot be rescued by NA. Analyses of NAPRT1 mRNA and protein levels in cell lines and primary tumor tissue indicate that high frequencies of glioblastomas, neuroblastomas, and sarcomas are deficient in NAPRT1 and not susceptible to rescue with NA. As a result, the therapeutic index of GMX1777 can be widended in the treatment animals bearing NAPRT1-deficient tumors by coadministration with NA. This provides the rationale for a novel therapeutic approach for the use of GMX1777 in the treatment of human cancers. PMID:19703994

  16. The small molecule GMX1778 is a potent inhibitor of NAD+ biosynthesis: strategy for enhanced therapy in nicotinic acid phosphoribosyltransferase 1-deficient tumors.

    PubMed

    Watson, Mark; Roulston, Anne; Bélec, Laurent; Billot, Xavier; Marcellus, Richard; Bédard, Dominique; Bernier, Cynthia; Branchaud, Stéphane; Chan, Helen; Dairi, Kenza; Gilbert, Karine; Goulet, Daniel; Gratton, Michel-Olivier; Isakau, Henady; Jang, Anne; Khadir, Abdelkrim; Koch, Elizabeth; Lavoie, Manon; Lawless, Michael; Nguyen, Mai; Paquette, Denis; Turcotte, Emilie; Berger, Alvin; Mitchell, Matthew; Shore, Gordon C; Beauparlant, Pierre

    2009-11-01

    GMX1777 is a prodrug of the small molecule GMX1778, currently in phase I clinical trials for the treatment of cancer. We describe findings indicating that GMX1778 is a potent and specific inhibitor of the NAD(+) biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT). Cancer cells have a very high rate of NAD(+) turnover, which makes NAD(+) modulation an attractive target for anticancer therapy. Selective inhibition by GMX1778 of NAMPT blocks the production of NAD(+) and results in tumor cell death. Furthermore, GMX1778 is phosphoribosylated by NAMPT, which increases its cellular retention. The cytotoxicity of GMX1778 can be bypassed with exogenous nicotinic acid (NA), which permits NAD(+) repletion via NA phosphoribosyltransferase 1 (NAPRT1). The cytotoxicity of GMX1778 in cells with NAPRT1 deficiency, however, cannot be rescued by NA. Analyses of NAPRT1 mRNA and protein levels in cell lines and primary tumor tissue indicate that high frequencies of glioblastomas, neuroblastomas, and sarcomas are deficient in NAPRT1 and not susceptible to rescue with NA. As a result, the therapeutic index of GMX1777 can be widended in the treatment animals bearing NAPRT1-deficient tumors by coadministration with NA. This provides the rationale for a novel therapeutic approach for the use of GMX1777 in the treatment of human cancers. PMID:19703994

  17. Effects of hypoxanthine substitution in peptide nucleic acids targeting KRAS2 oncogenic mRNA molecules: theory and experiment.

    PubMed

    Sanders, Jeffrey M; Wampole, Matthew E; Chen, Chang-Po; Sethi, Dalip; Singh, Amrita; Dupradeau, François-Yves; Wang, Fan; Gray, Brian D; Thakur, Mathew L; Wickstrom, Eric

    2013-10-01

    Genetic disorders can arise from single base substitutions in a single gene. A single base substitution for wild type guanine in the twelfth codon of KRAS2 mRNA occurs frequently to initiate lung, pancreatic, and colon cancer. We have observed single base mismatch specificity in radioimaging of mutant KRAS2 mRNA in tumors in mice by in vivo hybridization with radiolabeled peptide nucleic acid (PNA) dodecamers. We hypothesized that multimutant specificity could be achieved with a PNA dodecamer incorporating hypoxanthine, which can form Watson-Crick base pairs with adenine, cytosine, thymine, and uracil. Using molecular dynamics simulations and free energy calculations, we show that hypoxanthine substitutions in PNAs are tolerated in KRAS2 RNA:PNA duplexes where wild type guanine is replaced by mutant uracil or adenine in RNA. To validate our predictions, we synthesized PNA dodecamers with hypoxanthine, and then measured the thermal stability of RNA:PNA duplexes. Circular dichroism thermal melting results showed that hypoxanthine-containing PNAs are more stable in duplexes where hypoxanthine-adenine and hypoxanthine-uracil base pairs are formed than single mismatch duplexes or duplexes containing hypoxanthine-guanine opposition. PMID:23972113

  18. Effects of Hypoxanthine Substitution in Peptide Nucleic Acids Targeting KRAS2 Oncogenic mRNA Molecules: Theory and Experiment

    PubMed Central

    Sanders, Jeffrey M.; Wampole, Matthew E.; Chen, Chang-Po; Sethi, Dalip; Singh, Amrita; Dupradeau, François-Yves; Wang, Fan; Gray, Brian D.; Thakur, Mathew L.; Wickstrom, Eric

    2013-01-01

    Genetic disorders can arise from single base substitutions in a single gene. A single base substitution for wild type guanine in the twelfth codon of KRAS2 mRNA occurs frequently to initiate lung, pancreatic, and colon cancer. We have observed single base mismatch specificity in radioimaging of mutant KRAS2 mRNA in tumors in mice by in vivo hybridization with radiolabeled peptide nucleic acid (PNA) dodecamers. We hypothesized that multi-mutant specificity could be achieved with a PNA dodecamer incorporating hypoxanthine, which can form Watson-Crick basepairs with adenine, cytosine, thymine, and uracil. Using molecular dynamics simulations and free energy calculations, we show that hypoxanthine substitutions in PNAs are tolerated in KRAS2 RNA-PNA duplexes where wild type guanine is replaced by mutant uracil or adenine in RNA. To validate our predictions, we synthesized PNA dodecamers with hypoxanthine, and then measured the thermal stability of RNA-PNA duplexes. Circular dichroism thermal melting results showed that hypoxanthine-containing PNAs are more stable in duplexes where hypoxanthine-adenine and hypoxanthine-uracil base pairs are formed than single mismatch duplexes or duplexes containing hypoxanthine-guanine opposition. PMID:23972113

  19. On the reactivity of platinum(IV) complexes: Synthesis and spectroscopic studies of platinum(IV) complexes with hypoxanthine

    Microsoft Academic Search

    Akmal S. Gaballa

    2006-01-01

    Na2[PtCl6] was found to react with (HypH)Cl·H2O (2) (Hyp=hypoxanthine) in aqueous solution at room temperature yielding (HypH)2[PtCl6] (3). The same compound was obtained from hexachloroplatinic acid and hypoxanthine. Performing this reaction in methanol at 50 °C complex formation took place yielding the hypoxanthine complex [PtCl4(Hyp)2] (4). Both compounds were isolated in good yields as faint orange (3) and yellow (4)

  20. On the reactivity of platinum(IV) complexes: Synthesis and spectroscopic studies of platinum(IV) complexes with hypoxanthine

    Microsoft Academic Search

    Akmal S. Gaballa

    2006-01-01

    Na2[PtCl6] was found to react with (HypH)Cl·H2O (2) (Hyp=hypoxanthine) in aqueous solution at room temperature yielding (HypH)2[PtCl6] (3). The same compound was obtained from hexachloroplatinic acid and hypoxanthine. Performing this reaction in methanol at 50°C complex formation took place yielding the hypoxanthine complex [PtCl4(Hyp)2] (4). Both compounds were isolated in good yields as faint orange (3) and yellow (4) precipitates,

  1. Expression of Nicotinamide Phosphoribosyltransferase-Influenced Genes Predicts Recurrence-Free Survival in Lung and Breast Cancers

    PubMed Central

    Zhou, Tong; Wang, Ting; Garcia, Joe G. N.

    2014-01-01

    Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide biosynthesis. NAMPT protein is a secreted plasma biomarker in inflammation and in cancer. The NAMPT enzymatic inhibitor, FK866, acts as an inducer of apoptosis and is a cancer therapeutic candidate, however, little is known regarding the influence of NAMPT on cancer biological mechanisms or on the prognosis of human cancers. We interrogated known microarray data sets to define NAMPT knockdown-influenced gene expression to demonstrate that reduced NAMPT expression strongly dysregulates cancer biology signaling pathways. Comparisons of gene expression datasets of four cancer types generated a N39 molecular signature exhibiting consistent dysregulated expression in multiple cancer tissues. The N39 signature provides a significant and independent prognostic tool of human recurrence-free survival in lung and breast cancers. Despite the absence of clear elucidation of molecular mechanisms, this study validates NAMPT as a novel “oncogene” with a central role in carcinogenesis. Furthermore, the N39 signature provides a potentially useful tool for prediction of recurrence-free survival in lung and breast cancer and validates NAMPT as a novel and effective therapeutic target in cancer. PMID:25146220

  2. Crystallization and Preliminary X-Ray Crystallographic Studies of Escherichia coliXanthine Phosphoribosyltransferase

    Microsoft Academic Search

    Jennifer L. Martin

    1996-01-01

    Xanthine phosphoribosyltransferase (XPRT; EC 2.4.2.22) fromEscherichia coliis a purine salvage enzyme which synthesizes the nucleotides GMP, XMP, and IMP. A mutant C59A, which is more stable than wild-type XPRT while retaining high activity, has been prepared and crystallized to give three different crystal forms (A, B, and C). Form A crystals are orthorhombic (P21212), with unit cell dimensionsa= 59.2 Å,b=

  3. Inhibition of Nicotinamide Phosphoribosyltransferase (NAMPT), an Enzyme Essential for NAD+ Biosynthesis, Leads to Altered Carbohydrate Metabolism in Cancer Cells.

    PubMed

    Tan, Bo; Dong, Sucai; Shepard, Robert L; Kays, Lisa; Roth, Kenneth D; Geeganage, Sandaruwan; Kuo, Ming-Shang; Zhao, Genshi

    2015-06-19

    Nicotinamide phosphoribosyltransferase (NAMPT) has been extensively studied due to its essential role in NAD(+) biosynthesis in cancer cells and the prospect of developing novel therapeutics. To understand how NAMPT regulates cellular metabolism, we have shown that the treatment with FK866, a specific NAMPT inhibitor, leads to attenuation of glycolysis by blocking the glyceraldehyde 3-phosphate dehydrogenase step (Tan, B., Young, D. A., Lu, Z. H., Wang, T., Meier, T. I., Shepard, R. L., Roth, K., Zhai, Y., Huss, K., Kuo, M. S., Gillig, J., Parthasarathy, S., Burkholder, T. P., Smith, M. C., Geeganage, S., and Zhao, G. (2013) Pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT), an enzyme essential for NAD(+) biosynthesis, in human cancer cells: metabolic basis and potential clinical implications. J. Biol. Chem. 288, 3500-3511). Due to technical limitations, we failed to separate isotopomers of phosphorylated sugars. In this study, we developed an enabling LC-MS methodology. Using this, we confirmed the previous findings and also showed that NAMPT inhibition led to accumulation of fructose 1-phosphate and sedoheptulose 1-phosphate but not glucose 6-phosphate, fructose 6-phosphate, and sedoheptulose 7-phosphate as previously thought. To investigate the metabolic basis of the metabolite formation, we carried out biochemical and cellular studies and established the following. First, glucose-labeling studies indicated that fructose 1-phosphate was derived from dihydroxyacetone phosphate and glyceraldehyde, and sedoheptulose 1-phosphate was derived from dihydroxyacetone phosphate and erythrose via an aldolase reaction. Second, biochemical studies showed that aldolase indeed catalyzed these reactions. Third, glyceraldehyde- and erythrose-labeling studies showed increased incorporation of corresponding labels into fructose 1-phosphate and sedoheptulose 1-phosphate in FK866-treated cells. Fourth, NAMPT inhibition led to increased glyceraldehyde and erythrose levels in the cell. Finally, glucose-labeling studies showed accumulated fructose 1,6-bisphosphate in FK866-treated cells mainly derived from dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. Taken together, this study shows that NAMPT inhibition leads to attenuation of glycolysis, resulting in further perturbation of carbohydrate metabolism in cancer cells. The potential clinical implications of these findings are also discussed. PMID:25944913

  4. On the reactivity of platinum(IV) complexes: Synthesis and spectroscopic studies of platinum(IV) complexes with hypoxanthine

    NASA Astrophysics Data System (ADS)

    Gaballa, Akmal S.

    2006-01-01

    Na 2[PtCl 6] was found to react with (HypH)Cl·H 2O ( 2) (Hyp=hypoxanthine) in aqueous solution at room temperature yielding (HypH) 2[PtCl 6] ( 3). The same compound was obtained from hexachloroplatinic acid and hypoxanthine. Performing this reaction in methanol at 50 °C complex formation took place yielding the hypoxanthine complex [PtCl 4(Hyp) 2] ( 4). Both compounds were isolated in good yields as faint orange ( 3) and yellow ( 4) precipitates, respectively and characterized by microanalyses, IR and NMR ( 1H, 13C, 195Pt) spectroscopies as well as thermal analysis. Based on the data obtained an octahedral molecular structure is proposed for complex 4 with two hypoxanthine ligands coordinated through N7 to platinum(IV).

  5. Mutagenesis in human cells with accelerated H and Fe ions

    NASA Technical Reports Server (NTRS)

    Kronenberg, Amy

    1994-01-01

    The overall goals of this research were to determine the risks of mutation induction and the spectra of mutations induced by energetic protons and iron ions at two loci in human lymphoid cells. During the three year grant period the research has focused in three major areas: (1) the acquisition of sufficient statistics for human TK6 cell mutation experiments using Fe ions (400 MeV/amu), Fe ions (600 MeV/amu) and protons (250 MeV/amu); (2) collection of thymidine kinase- deficient (tk) mutants or hypoxanthine phosphoribosyltransferase deficient (hprt) mutants induced by either Fe 400 MeV/amu, Fe 600 MeV/amu, or H 250 MeV/amu for subsequent molecular analysis; and (3) molecular characterization of mutants isolated after exposure to Fe ions (600 MeV/amu). As a result of the shutdown of the BEVALAC heavy ion accelerator in December 1992, efforts were rearranged somewhat in time to complete our dose-response studies and to complete mutant collections in particular for the Fe ion beams prior to the shutdown. These goals have been achieved. A major effort was placed on collection, re-screening, and archiving of 3 different series of mutants for the various particle beam exposures: tk-ng mutants, tk-sg mutants, and hprt-deficient mutants. Where possible, groups of mutants were isolated for several particle fluences. Comparative analysis of mutation spectra has occured with characterization of the mutation spectrum for hprt-deficient mutants obtained after exposure of TK6 cells to Fe ions (600 MeV/amu) and a series of spontaneous mutants.

  6. Genetic Regulation of Charged Particle Mutagenesis in Human Cells

    NASA Technical Reports Server (NTRS)

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

    1999-01-01

    Our studies use a series of syngeneic, and where possible, isogenic human B-lymphoblastoid cell lines to assess the genetic factors that modulate susceptibility apoptosis and their impact on the mutagenic risks of low fluence exposures to 1 GeV Fe ions and 55 MeV protons. These ions are representative of the types of charged particle radiation that are of particular significance for human health in the space radiation environment. The model system employs cell lines derived from the male donor WIL-2. These cells have a single X chromosome and they are hemizygous for one mutation marker, hypoxanthine phosphoribosyltransferase (HPRT). TK6 and WTK1 cells were each derived from descendants of WIL-2 and were each selected as heterozygotes for a second mutation marker, the thymidine kinase (TK) gene located on chromosome 17q. The HPRT and TK loci can detect many different types of mutations, from single basepair substitutions up to large scale loss of heterozygosity (LOH). The single expressing copy of TK in the TK6 and WTKI cell lines is found on the same copy of chromosome 17, and this allele can be identified by a restriction fragment length polymorphism (RFLP) identified when high molecular weight DNA is digested by the SacI restriction endonuclease and hybridized against the cDNA probe for TK. A large series of polymorphic linked markers has been identified that span more than 60 cM of DNA (approx. 60 megabasepairs) and distinguish the copy of chromosome 17 bearing the initially active TK allele from the copy of chromosome 17 bearing the silent TK allele in both TK6 and WTKI cells. TK6 cells express normal p53 protein while WTKI cells express homozygous mutant p53. Expression of mutant p53 can increase susceptibility to x-ray-induced mutations. It's been suggested that the increased mutagenesis in p53 mutant cells might be due to reduced apoptosis.

  7. Epstein-Barr virus shuttle vector for stable episomal replication of cDNA expression libraries in human cells.

    PubMed Central

    Margolskee, R F; Kavathas, P; Berg, P

    1988-01-01

    Efficient transfection and expression of cDNA libraries in human cells has been achieved with an Epstein-Barr virus-based subcloning vector (EBO-pcD). The plasmid vector contains a resistance marker for hygromycin B to permit selection for transformed cells. The Epstein-Barr virus origin for plasmid replication (oriP) and the Epstein-Barr virus nuclear antigen gene have also been incorporated into the vector to ensure that the plasmids are maintained stably and extrachromosomally. Human lymphoblastoid cells can be stably transformed at high efficiency (10 to 15%) by such plasmids, thereby permitting the ready isolation of 10(6) to 10(7) independent transformants. Consequently, entire high-complexity EBO-pcD expression libraries can be introduced into these cells. Furthermore, since EBO-pcD plasmids are maintained as episomes at two to eight copies per cell, intact cDNA clones can be readily isolated from transformants and recovered by propagation in Escherichia coli. By using such vectors, human cells have been stably transformed with EBO-pcD-hprt to express hypoxanthine-guanine phosphoribosyltransferase and with EBO-pcD-Leu-2 to express the human T-cell surface marker Leu-2 (CD8). Reconstruction experiments with mixtures of EBO-pcD plasmids demonstrated that one clone of EBO-pcD-hprt per 10(6) total clones or one clone of EBO-pcD-Leu-2 per 2 x 10(4) total clones can be recovered intact from the transformed cells. The ability to directly select for expression of very rare EBO-pcD clones and to then recover these episomes should make it possible to clone certain genes where hybridization and immunological screening methods are not applicable but where a phenotype can be scored or selected in human cell lines. Images PMID:2841588

  8. The gene for theta-globin is transcribed in human fetal erythroid tissues.

    PubMed

    Leung, S; Proudfoot, N J; Whitelaw, E

    A new gene like the alpha-globin gene has been identified in higher primates at the 3' end of the alpha-globin gene cluster. There is some controversy as to whether this gene, theta, is a functional globin gene or a non-functional pseudogene. The high degree of sequence conservation displayed by theta between primates and various mammals, such as horse and rabbit, suggests that this gene is functional in some species. Furthermore, theta encodes a 141-amino-acid polypeptide in sequence similar to alpha-globin and appears to possess functional RNA-processing signals. But the promoter region of theta is unlike the other globin genes because its CCAAT and ATA box sequences are displaced from the coding sequence by the insertion of a 200-base-pair GC-rich sequence. We demonstrate here the presence of theta-globin messenger RNA in human fetal erythroid tissue, but not in adult erythroid or other non-erythroid tissues. Furthermore, theta-globin mRNA is detectable in significant amounts in a human erythroleukaemic cell line. These results predict that theta-globin protein will be found in the early stages of human fetal development. Surprisingly, the promoter sequence of theta-globin does not correspond to the CCAAT and ATA box sequences of the gene but rather lies within the adjacent GC-rich sequence, resulting in a heterogeneous series of mRNA 5' ends 50-10 base pairs to 5' of the initiation codon. This type of promoter is reminiscent of that found in housekeeping genes such as adenine deaminase and hypoxanthine-guanine phosphoribosyl-transferase. PMID:3657976

  9. UV Radiation Induces Delayed Hyperrecombination Associated with Hypermutation in Human Cells†

    PubMed Central

    Durant, Stephen T.; Paffett, Kimberly S.; Shrivastav, Meena; Timmins, Graham S.; Morgan, William F.; Nickoloff, Jac A.

    2006-01-01

    Ionizing radiation induces delayed genomic instability in human cells, including chromosomal abnormalities and hyperrecombination. Here, we investigate delayed genome instability of cells exposed to UV radiation. We examined homologous recombination-mediated reactivation of a green fluorescent protein (GFP) gene in p53-proficient human cells. We observed an ?5-fold enhancement of delayed hyperrecombination (DHR) among cells surviving a low dose of UV-C (5 J/m2), revealed as mixed GFP+/? colonies. UV-B did not induce DHR at an equitoxic (75 J/m2) dose or a higher dose (150 J/m2). UV is known to induce delayed hypermutation associated with increased oxidative stress. We found that hypoxanthine phosphoribosyltransferase (HPRT) mutation frequencies were ?5-fold higher in strains derived from GFP+/? (DHR) colonies than in strains in which recombination was directly induced by UV (GFP+ colonies). To determine whether hypermutation was directly caused by hyperrecombination, we analyzed hprt mutation spectra. Large-scale alterations reflecting large deletions and insertions were observed in 25% of GFP+ strains, and most mutants had a single change in HPRT. In striking contrast, all mutations arising in the hypermutable GFP+/? strains were small (1- to 2-base) changes, including substitutions, deletions, and insertions (reminiscent of mutagenesis from oxidative damage), and the majority were compound, with an average of four hprt mutations per mutant. The absence of large hprt deletions in DHR strains indicates that DHR does not cause hypermutation. We propose that UV-induced DHR and hypermutation result from a common source, namely, increased oxidative stress. These two forms of delayed genome instability may collaborate in skin cancer initiation and progression. PMID:16880516

  10. Nicotinamide phosphoribosyltransferase inhibitor is a novel therapeutic candidate in murine models of inflammatory lung injury.

    PubMed

    Moreno-Vinasco, Liliana; Quijada, Hector; Sammani, Saad; Siegler, Jessica; Letsiou, Eleftheria; Deaton, Ryan; Saadat, Laleh; Zaidi, Rafe S; Messana, Joe; Gann, Peter H; Machado, Roberto F; Ma, Wenli; Camp, Sara M; Wang, Ting; Garcia, Joe G N

    2014-08-01

    We previously identified the intracellular nicotinamide phosphoribosyltransferase (iNAMPT, aka pre-B-cell colony enhancing factor) as a candidate gene promoting acute respiratory distress syndrome (ARDS) and ventilator-induced lung injury (VILI) with circulating nicotinamide phosphoribosyltransferase potently inducing NF-?B signaling in lung endothelium. iNAMPT also synthesizes intracellular nicotinamide adenine dinucleotide (iNAD) in response to extracellular oxidative stress, contributing to the inhibition of apoptosis via ill-defined mechanisms. We now further define the role of iNAMPT activity in the pathogenesis of ARDS/VILI using the selective iNAMPT inhibitor FK-866. C57/B6 mice were exposed to VILI (40 ml/kg, 4 h) or LPS (1.5 mg/kg, 18 h) after osmotic pump delivery of FK-866 (100 mg/kg/d, intraperitoneally). Assessment of total bronchoalveolar lavage (BAL) protein, polymorphonuclear neutrophil (PMN) levels, cytokine levels (TNF-?, IL-6, IL-1?), lung iNAD levels, and injury scores revealed that FK-866-mediated iNAMPT inhibition successfully reduced lung tissue iNAD levels, BAL injury indices, inflammatory cell infiltration, and lung injury scores in LPS- and VILI-exposed mice. FK-866 further increased lung PMN apoptosis, as reflected by caspase-3 activation in BAL PMNs. These findings support iNAMPT inhibition via FK-866 as a novel therapeutic agent for ARDS via enhanced apoptosis in inflammatory PMNs. PMID:24588101

  11. Photoion mass spectroscopy and valence photoionization of hypoxanthine, xanthine and caffeine

    NASA Astrophysics Data System (ADS)

    Feyer, Vitaliy; Plekan, Oksana; Richter, Robert; Coreno, Marcello; Prince, Kevin C.

    2009-03-01

    Photoionization mass spectra of hypoxanthine, xanthine and caffeine were measured using the photoelectron-photoion coincidence technique and noble gas resonance radiation at energies from 8.4 to 21.2 eV for ionization. The fragmentation patterns for these compounds show that hydrogen cyanide is the main neutral loss species at higher photon energies, while photoionization below 16.67 eV led predominantly to the parent ion. The valence photoelectron spectra of this family of molecules were measured over an extended energy range, including the inner C, N and O 2s valence orbitals. The observed ion fragments were related to ionization of the valence orbitals.

  12. Pharmacological Inhibition of Nicotinamide Phosphoribosyltransferase\\/Visfatin Enzymatic Activity Identifies a New Inflammatory Pathway Linked to NAD

    Microsoft Academic Search

    Nathalie Busso; Mahir Karababa; Massimo Nobile; Aline Rolaz; Frédéric van Gool; Mara Galli; Oberdan Leo; Alexander So; Thibaut de Smedt; Jacques Zimmer

    2008-01-01

    Nicotinamide phosphoribosyltransferase (NAMPT), also known as visfatin, is the rate-limiting enzyme in the salvage pathway of NAD biosynthesis from nicotinamide. Since its expression is upregulated during inflammation, NAMPT represents a novel clinical biomarker in acute lung injury, rheumatoid arthritis, and Crohn's disease. However, its role in disease progression remains unknown. We report here that NAMPT is a key player in

  13. Carbon nanospheres enhanced electrochemiluminescence of CdS quantum dots for biosensing of hypoxanthine.

    PubMed

    Zhang, Yangyang; Deng, Shengyuan; Lei, Jianping; Xu, Qiunan; Ju, Huangxian

    2011-09-30

    This work developed a novel method to greatly enhance the electrochemiluminescence (ECL) of CdS quantum dots (QDs). The ECL amplification was achieved by the assembly of QDs on poly (diallyldimethylammonium chloride)-functionalized carbon nanospheres (PFCNSs), and successfully employed for sensitive ECL biosensing of oxidase substrates. The carbon nanospheres were prepared by a "green" method, and the high loading of QDs on carbon nanospheres led to a 4-times increased ECL intensity with dissolved O(2) as the coreactant. Using xanthine oxidase (XOD) as a model, an ECL biosensor was fabricated by immobilizing the enzyme on the mixing membrane of PFCNSs and QDs. The ECL biosensor showed a fast response to hypoxanthine with a linear concentration range from 2.5 × 10(-8) to 1.4 × 10(-5)M. The limit of detection was 5 nM at a signal-to-noise ratio of 3. The assay results of hypoxanthine in fish samples were in a good agreement with the reference values by amperometric technique. This facile approach to prepare the PFCNSs/QDs system for ECL biosensing could be of promising application in bioanalysis and electronic device. PMID:21872072

  14. Mutagenesis and cytotoxicity in human epithelial cells by far- and near-ultraviolet radiations: action spectra

    SciTech Connect

    Jones, C.A.; Huberman, E.; Cunningham, M.L.; Peak, M.J.

    1987-05-01

    Action spectra were determined for cell killing and mutation by monochromatic ultraviolet and visible radiations (254-434 nm) in cultured human epithelial P3 cells. Cell killing was more efficient following radiation at the shorter wavelengths (254-434 nm) than at longer wavelengths (365-434 nm). At 254 nm, for example, a fluence of 11 Jm-2 gave 37% cell survival, while at 365 nm, 17 X 10(5) Jm-2 gave equivalent survival. At 434 nm little killing was observed with fluences up to 3 X 10(6) Jm-2. Mutant induction, determined at the hypoxanthine-guanine phosphoribosyltransferase locus, was caused by radiation at 254, 313, and 365 nm. There was no mutant induction at 334 nm although this wavelength was highly cytotoxic. Mutagenesis was not induced by 434 nm radiation, either. There was a weak response at 405 nm; the mutant frequencies were only slightly increased above background levels. For the mutagenic wavelengths, log-log plots of the mutation frequency against fluence showed linear regressions with positive slopes of 2.5, consistent with data from a previous study using Escherichia coli. The data points of the action spectra for lethality and mutagenesis were similar to the spectrum for DNA damage at wavelengths shorter than 313 nm, whereas at longer wavelengths the lethality spectrum had a shoulder, and the mutagenesis spectrum had a secondary peak at 365 nm. No correlation was observed for the P3 cells between the spectra for cell killing and mutagenesis caused by wavelengths longer than 313 nm and the induction of DNA breakage or the formation of DNA-to-protein covalent bonds in these cells.

  15. Nicotinamide phosphoribosyltransferase (Nampt): a link between NAD biology, metabolism, and diseases.

    PubMed

    Imai, Shin-Ichiro

    2009-01-01

    New interest in NAD biology has recently been revived, and enzymes involved in NAD biosynthetic pathways have been identified and characterized in mammals. Among them, nicotinamide phosphoribosyltransferase (Nampt) has drawn much attention in several different fields, including NAD biology, metabolism, and immunomodulatory response. The research history of this protein is peculiar and controversial, and its physiological function has been a matter of debate. Nampt has both intra- and extracellular forms in mammals. Intracellular Nampt (iNampt) is an essential enzyme in the NAD biosynthetic pathway starting from nicotinamide. On the other hand, an extracellular form of this protein has been reported to act as a cytokine named PBEF, an insulin-mimetic hormone named visfatin, or an extracellular NAD biosynthetic enzyme named eNampt. This review article summarizes the research history and reported functions of this unique protein and discusses the pathophysiological significance of Nampt as an NAD biosynthetic enzyme vs. a potential inflammatory cytokine in diverse biological contexts. PMID:19149599

  16. Analysis of oxonic acid, uric acid, creatine, allantoin, xanthine and hypoxanthine in poultry litter by reverse phase HPLC

    Microsoft Academic Search

    M. A. Eiteman; R. M. Gordillo; M. L. Cabrera

    1994-01-01

    A separation method has been developed to extract organic compounds from poultry manure and litter and subsequently analyze these extracts using reverse phase high-pressure liquid chromatography. Specifically, the method may be used to quantify oxonic acid, allantoin, creatine, uric acid, xanthine and hypoxanthine in poultry manure samples. In a representative sample of fresh poultry manure, oxonic acid, allantoin, creatine, uric

  17. Determination of Xanthine in the Presence of Hypoxanthine by Adsorptive Stripping Voltammetry at the Mercury Film Electrode

    PubMed Central

    Farias, Percio Augusto Mardini; Castro, Arnaldo Aguiar

    2014-01-01

    A stripping method for the determination of xanthine in the presence of hypoxanthine at the submicromolar concentration levels is described. The method is based on controlled adsorptive accumulation at the thin-film mercury electrode followed by a fast linear scan voltammetric measurement of the surface species. Optimum experimental conditions were found to be the use of 1.0 × 10?3 mol L?1 NaOH solution as supporting electrolyte, an accumulation potential of 0.00 V for xanthine and ?0.50 V for hypoxanthine–copper, and a linear scan rate of 200 mV second?1. The response of xanthine is linear over the concentration ranges of 20–140 ppb. For an accumulation time of 30 minutes, the detection limit was found to be 36 ppt (2.3 × 10?10 mol L?1). Adequate conditions for measuring the xanthine in the presence of hypoxanthine, copper and other metals, uric acid, and other nitrogenated bases were also investigated. The utility of the method is demonstrated by the presence of xanthine associated with hypoxanthine, uric acid, nitrogenated bases, ATP, and ssDNA. PMID:24940040

  18. Overexpression of the Orotate Phosphoribosyl-Transferase Gene Enhances the Effect of 5Fluorouracil on Gastric Cancer Cell Lines

    Microsoft Academic Search

    Jyunnya Taomoto; Kazuhiro Yoshida; Yoshiyuki Wada; Kazuaki Tanabe; Kazuo Konishi; Hidetoshi Tahara; Masakazu Fukushima

    2006-01-01

    Objective: Orotate phosphoribosyl-transferase (OPRT) is the initial enzyme of the 5-fluorouracil (5-FU) metabolic pathway, converting 5-FU into 5-fluorouridinemonophosphate, which is the most important mechanism of 5-FU activation. We therefore investigated whether overexpression of the OPRT gene enhances sensitivity to 5-FU. Methods: An expression vector of the OPRT gene (pTARGET-OPRT) was transfected into two gastric cancer cell lines, TMK-1 and MKN-45,

  19. Substrate Orientation and Catalytic Specificity in the Action of Xanthine Oxidase: The Sequential Hydroxylation of Hypoxanthine to Uric Acid

    SciTech Connect

    Cao, Hongnan; Pauff, James M.; Hille, Russ (UCR)

    2010-11-29

    Xanthine oxidase is a molybdenum-containing enzyme catalyzing the hydroxylation of a sp{sup 2}-hybridized carbon in a broad range of aromatic heterocycles and aldehydes. Crystal structures of the bovine enzyme in complex with the physiological substrate hypoxanthine at 1.8 {angstrom} resolution and the chemotherapeutic agent 6-mercaptopurine at 2.6 {angstrom} resolution have been determined, showing in each case two alternate orientations of substrate in the two active sites of the crystallographic asymmetric unit. One orientation is such that it is expected to yield hydroxylation at C-2 of substrate, yielding xanthine. The other suggests hydroxylation at C-8 to give 6,8-dihydroxypurine, a putative product not previously thought to be generated by the enzyme. Kinetic experiments demonstrate that >98% of hypoxanthine is hydroxylated at C-2 rather than C-8, indicating that the second crystallographically observed orientation is significantly less catalytically effective than the former. Theoretical calculations suggest that enzyme selectivity for the C-2 over C-8 of hypoxanthine is largely due to differences in the intrinsic reactivity of the two sites. For the orientation of hypoxanthine with C-2 proximal to the molybdenum center, the disposition of substrate in the active site is such that Arg880 and Glu802, previous shown to be catalytically important for the conversion of xanthine to uric acid, play similar roles in hydroxylation at C-2 as at C-8. Contrary to the literature, we find that 6,8-dihydroxypurine is effectively converted to uric acid by xanthine oxidase.

  20. Simultaneous measurement of allantoin, uric acid, xanthine and hypoxanthine in blood by high-performance liquid chromatography

    Microsoft Academic Search

    M Czauderna; J Kowalczyk

    1997-01-01

    A high-performance liquid chromatographic method for determining catabolism products of nucleic acids and purines, such as oxypurines (i.e. uric acid, xanthine and hypoxanthine) and allantoin in the blood plasma of ruminants was developed. The plasma was deproteinized with 10% trichloroacetic acid. The method enabled determination of oxypurines without derivatization. Allantoin was determined after conversion with 2,4-dinitrophenylhydrazine to a hydrazone (GLX-DNPH).

  1. The hpx genetic system for hypoxanthine assimilation as a nitrogen source in Klebsiella pneumoniae: gene organization and transcriptional regulation.

    PubMed

    de la Riva, Lucia; Badia, Josefa; Aguilar, Juan; Bender, Robert A; Baldoma, Laura

    2008-12-01

    Growth experiments showed that adenine and hypoxanthine can be used as nitrogen sources by several strains of K. pneumoniae under aerobic conditions. The assimilation of all nitrogens from these purines indicates that the catabolic pathway is complete and proceeds past allantoin. Here we identify the genetic system responsible for the oxidation of hypoxanthine to allantoin in K. pneumoniae. The hpx cluster consists of seven genes, for which an organization in four transcriptional units, hpxDE, hpxR, hpxO, and hpxPQT, is proposed. The proteins involved in the oxidation of hypoxanthine (HpxDE) or uric acid (HpxO) did not display any similarity to other reported enzymes known to catalyze these reactions but instead are similar to oxygenases acting on aromatic compounds. Expression of the hpx system is activated by nitrogen limitation and by the presence of specific substrates, with hpxDE and hpxPQT controlled by both signals. Nitrogen control of hpxPQT transcription, which depends on sigma(54), is mediated by the Ntr system. In contrast, neither NtrC nor the nitrogen assimilation control protein is involved in the nitrogen control of hpxDE, which is dependent on sigma(70) for transcription. Activation of these operons by the specific substrates is also mediated by different effectors and regulatory proteins. Induction of hpxPQT requires uric acid formation, whereas expression of hpxDE is induced by the presence of hypoxanthine through the regulatory protein HpxR. This LysR-type regulator binds to a TCTGC-N(4)-GCAAA site in the intergenic hpxD-hpxR region. When bound to this site for hpxDE activation, HpxR negatively controls its own transcription. PMID:18849434

  2. High variation in hypoxanthine determination after analytical treatment of vitreous humor samples.

    PubMed

    Camba, Ana; Lendoiro, Elena; Cordeiro, Cristina; Martínez-Silva, Isabel; Rodríguez-Calvo, María S; Vieira, Duarte N; Muñoz-Barús, José I

    2014-12-01

    In the field of legal medicine the correct determination of the time of death is of great importance because an error in calculating the post-mortem interval (PMI) could be crucial in a criminal investigation. The quantification of hypoxanthine (Hx) concentration in the vitreous humor (VH) as a means to estimate PMI is useful when dealing with a recent time interval of death and has several advantages over other biological matrices. However, due to its viscous nature, VH has to be liquefied prior to its analysis, and the different procedures to liquefy it may cause alterations in Hx concentration, and hence in estimation of PMI. The aim of this study was to determine differences in Hx concentration after applying several pre-analytical treatments to different aliquots of the same VH sample. Enzymatic digestion, sonication, centrifugation and heat were the liquefying methods applied to reduce the viscosity of 105 VH samples. Analysis was performed using solid phase extraction and liquid chromatography in tandem with mass spectrometry. Statistically significant differences in the measured Hx concentrations were found between enzymatic digestion and the other three methods analyzed (sonication, centrifugation, and heat). Additionally, high data dispersion was found under heat treatment but was not observed for centrifugation or sonication, where similar and more moderate results were found. We conclude that high variations in Hx determination are observed when enzymatic digestion or heat treatment is used and we therefore recommend sonication or centrifugation to quantify Hx concentration in the VH. PMID:25119241

  3. Nicotinamide phosphoribosyltransferase inhibition reduces intraplaque CXCL1 production and associated neutrophil infiltration in atherosclerotic mice.

    PubMed

    Nencioni, Alessio; da Silva, Rafaela F; Fraga-Silva, Rodrigo A; Steffens, Sabine; Fabre, Mathias; Bauer, Inga; Caffa, Irene; Magnone, Mirko; Sociali, Giovanna; Quercioli, Alessandra; Pelli, Graziano; Lenglet, Sébastien; Galan, Katia; Burger, Fabienne; Vázquez Calvo, Sara; Bertolotto, Maria; Bruzzone, Santina; Ballestrero, Alberto; Patrone, Franco; Dallegri, Franco; Santos, Robson A; Stergiopulos, Nikolaos; Mach, François; Vuilleumier, Nicolas; Montecucco, Fabrizio

    2014-02-01

    Pharmacological treatments targeting CXC chemokines and the associated neutrophil activation and recruitment into atherosclerotic plaques hold promise for treating cardiovascular disorders. Therefore, we investigated whether FK866, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with anti-inflammatory properties that we recently found to reduce neutrophil recruitment into the ischaemic myocardium, would exert beneficial effects in a mouse atherosclerosis model. Atherosclerotic plaque formation was induced by carotid cast implantation in ApoE-/- mice that were fed with a Western-type diet. FK866 or vehicle were administrated intraperitoneally from week 8 until week 11 of the diet. Treatment with FK866 reduced neutrophil infiltration and MMP-9 content and increased collagen levels in atherosclerotic plaques compared to vehicle. No effect on other histological parameters, including intraplaque lipids or macrophages, was observed. These findings were associated with a reduction in both systemic and intraplaque CXCL1 levels in FK866-treated mice. In vitro, FK866 did not affect MMP-9 release by neutrophils, but it strongly reduced CXCL1 production by endothelial cells which, in the in vivo model, were identified as a main CXCL1 source at the plaque level. CXCL1 synthesis inhibition by FK866 appears to reflect interference with nuclear factor-?B signalling as shown by reduced p65 nuclear levels in endothelial cells pre-treated with FK866. In conclusion, pharmacological inhibition of NAMPT activity mitigates inflammation in atherosclerotic plaques by reducing CXCL1-mediated activities on neutrophils. These results support further assessments of NAMPT inhibitors for the potential prevention of plaque vulnerability. PMID:24196571

  4. Nicotinamide phosphoribosyltransferase regulates cell survival through NAD+ synthesis in cardiac myocytes

    PubMed Central

    Hsu, Chiao-Po; Oka, Shinichi; Shao, Dan; Hariharan, Nirmala; Sadoshima, Junichi

    2009-01-01

    Rationale NAD+ acts not only as a co-factor for cellular respiration, but also as a substrate for NAD+-dependent enzymes, such as Sirt1. The cellular NAD+ synthesis is regulated by both the de novo and the salvage pathways. Nicotinamide phosphoribosyltransferase (Nampt) is a rate-limiting enzyme in the salvage pathway. Objective Here we investigated the role of Nampt in mediating NAD+ synthesis in cardiac myocytes and the function of Nampt in the heart in vivo. Methods and Results Expression of Nampt in the heart was significantly decreased by ischemia, ischemia/reperfusion and pressure overload. Upregulation of Nampt significantly increased NAD+ and ATP concentrations, while downregulation of Nampt significantly decreased them. Downregulation of Nampt increased caspase 3 cleavage, cytochrome c release, and TUNEL positive cells, which were inhibited in the presence of Bcl-xL, but did not increase hairpin 2 positive cells, suggesting that endogenous Nampt negatively regulates apoptosis but not necrosis. Downregulation of Nampt also impaired autophagic flux, suggesting that endogenous Nampt positively regulates autophagy. Cardiac specific overexpression of Nampt in transgenic mice increased NAD+ content in the heart, prevented downregulation of Nampt and reduced the size of myocardial infarction and apoptosis in response to prolonged ischemia and ischemia/reperfusion. Conclusions Nampt critically regulates NAD+ and ATP contents, thereby playing an essential role in mediating cell survival by inhibiting apoptosis and stimulating autophagic flux in cardiac myocytes. Preventing downregulation of Nampt inhibits myocardial injury in response to myocardial ischemia and reperfusion. These results suggest that Nampt is an essential gatekeeper of energy status and survival in cardiac myocytes. PMID:19661458

  5. Transport of [14C]hypoxanthine by sheep choroid plexus epithelium as a monolayer in primary culture: Na+-dependent and Na+-independent uptake by the apical membrane and rapid intracellular metabolic conversion to nucleotides.

    PubMed

    Isakovic, Aleksandra J; Dencic, Sonja Misirlic; Segal, Malcolm B; Redzic, Zoran B

    2008-01-31

    Hypoxanthine is the main product of purine metabolic degradation and previous studies have revealed that it is present in the sheep CSF and plasma in micromolar concentrations. The aim of this study was to elucidate the transport of this molecule across the sheep choroid plexus epithelium (CPE) as a monolayer in primary culture, to explore the mechanism of uptake by the apical side of the CPE and investigate the metabolic changes inside the cell. The estimated permeability of the CPE monolayer for [14C]hypoxanthine, [14C]adenine and [14C]guanine was low and comparable to the permeability towards the extracellular space markers. The study of [14C]hypoxanthine uptake by the CPE revealed two components: Na+-dependent and Na+-independent, the latter being partially mediated by the equilibrative nucleoside transporter 2. HPLC with simultaneous detection of radioactivity revealed that the majority of [14C]hypoxanthine inside the CPE is metabolised into [14C]nucleotides and [14C]inosine. The remaining intact [14C]hypoxanthine was transported across the opposite, basolateral side of CPE and appeared in the lower chamber buffer together with [14C]inosine. These findings indicate two possible roles of hypoxanthine uptake from the CSF by the CP epithelium in vivo: to provide material for nucleotide synthesis through the salvage pathways in the CPE, as well as to transfer excess hypoxanthine from CSF to blood. PMID:18164814

  6. Sensitivity of somatic mutations in human umbilical cord blood to maternal environments

    SciTech Connect

    Manchester, D.K. [Childrens Hospital and Univ. of Colorado School of Medicine, Denver, CO (United States); Nicklas, J.A.; O`Neill, J.P. [Univ. of Vermont, Burlington, VT (United States)] [and others

    1995-12-31

    To assess the potential effect of maternal environments on human embryonic/fecal somatic mutation, we measured the frequencies of hypoxanthine-guanine phosphoribosyltransferase (HPRT, hprt gene), mutant T lymphocytes (M{sub f}) and glycophorin A (GPA) variant erythrocytes (V{sub f}) of both allele-loss ({phi}/N) and allele-loss-and duplication (N/N) phenotypes in umbilical cord blood. The mean hprt M{sub F} were significantly lower than those previously reported for adult populations. In addition, the hprt M{sub f} was significantly higher than that of a published study of newborn cord blood samples from a geographically distant population (0.64 {+-} 0.41 x 10{sup -6}, N = 45, P < 0.01; t test, P < 0.01, Mann-Whitney U test). An examination of the demographic data from these two populations led to the sampling of 10 additional newborns specifically matched to the published study for maternal socioeconomic status. The hprt M{sub f} (0.70 {+-} 0.49 x 10{sup -6}) of this selected population was consistent with the published report and significantly lower than that of our initial population (P < 0.03, t test; P < 0.01, Mann-Whitney U test). These results indicate that there is an environmental effect related to maternal socioeconomic status of the frequency of embryonic/fetal somatic mutations. Molecular analyses of hprt mutants from this cohort with elevated M{sub f} revealed a significant decrease in the relative contribution of gross structural mutations to the overall M{sub f} (25 of 38, 66% vs. 34 of 41, 83%, P = 0.024, {chi}{sup 2} test), suggesting that the higher M{sub f} resulted from an elevated level of {open_quotes}point{close_quotes} mutations. No individual maternal demographic or environmental factor was identified as contributing more significantly than any other factor to the observed variability in hprt M{sub f} or GPA V{sub f}. 43 refs., 4 tabs.

  7. Bisphosphonates activate the 5-fluorouracil/uracil phosphoribosyltransferase activity present in Saccharomyces cerevisiae cell extracts: implications for tumor treatments.

    PubMed

    Pérez-Zúñiga, Francisco J; Günther Sillero, María A; Sillero, Antonio

    2008-10-01

    Most of the effects described for bisphosphonates (pC(R1)(R2)p) are related, directly or indirectly with a pyrophosphate moiety. Bisphosphonates are (i) analogs of pyrophosphate in the synthesis of ATP derivatives (AppC(R1)(R2)p) catalyzed by ligases and (ii) inhibitors of enzymes of the mevalonate pathway with substrates containing a terminal pyrophosphate. Searching for the role of bisphosphonates on other reactions involving pyrophosphate, we explored their effect on a phosphoribosyltransferase activity, present in Saccharomyces cerevisiae cell extracts, using 5-fluorouracil or uracil as substrates. Unexpectedly, bisphosphonates increased the initial rate of synthesis of 5-FUMP (from 5-fluorouracil and phosphoribosylpyrophosphate): etidronate (2.8+/-0.3 times); pamidronate (2.6+/-0.4 times); alendronate (2.5+/-0.6 times) and clodronate (2.0+/-0.1 times). Similar values for the synthesis of UMP (from uracil and phosphoribosylpyrophosphate) were obtained in the presence of bisphosphonates. The values of the activation constants determined for alendronate and clodronate for the synthesis of UMP were 0.05+/-0.02 mM and 0.32+/-0.22 mM, respectively. These results raise the possibility that bisphosphonates enhance the effect of 5-fluorouracil (or other uracil prodrugs) in the treatment of bone tumors or bone tumor metastases. PMID:18706399

  8. Pharmacological Inhibition of Nicotinamide Phosphoribosyltransferase/Visfatin Enzymatic Activity Identifies a New Inflammatory Pathway Linked to NAD

    PubMed Central

    Nobile, Massimo; Rolaz, Aline; Van Gool, Frédéric; Galli, Mara; Leo, Oberdan; So, Alexander; De Smedt, Thibaut

    2008-01-01

    Nicotinamide phosphoribosyltransferase (NAMPT), also known as visfatin, is the rate-limiting enzyme in the salvage pathway of NAD biosynthesis from nicotinamide. Since its expression is upregulated during inflammation, NAMPT represents a novel clinical biomarker in acute lung injury, rheumatoid arthritis, and Crohn's disease. However, its role in disease progression remains unknown. We report here that NAMPT is a key player in inflammatory arthritis. Increased expression of NAMPT was confirmed in mice with collagen-induced arthritis, both in serum and in the arthritic paw. Importantly, a specific competitive inhibitor of NAMPT effectively reduced arthritis severity with comparable activity to etanercept, and decreased pro-inflammatory cytokine secretion in affected joints. Moreover, NAMPT inhibition reduced intracellular NAD concentration in inflammatory cells and circulating TNF? levels during endotoxemia in mice. In vitro pharmacological inhibition of NAMPT reduced the intracellular concentration of NAD and pro-inflammatory cytokine secretion by inflammatory cells. Thus, NAMPT links NAD metabolism to inflammatory cytokine secretion by leukocytes, and its inhibition might therefore have therapeutic efficacy in immune-mediated inflammatory disorders. PMID:18493620

  9. Amperometric detection of uric acid and hypoxanthine with Xanthine oxidase immobilized and carbon based screen-printed electrode. Application for fish freshness determination

    Microsoft Academic Search

    M. A. Carsol; G. Volpe; M. Mascini

    1997-01-01

    Carbon-based screen-printed electrodes are suitable for uric acid detection. Xanthine oxidase (XO) was immobilized either directly on the surface of the electrode or in a reactor with CPG aminopropylsilane in a FIA assembly. Higher reproducibility and lifetime was obtained with the reactor. Optimum conditions were found for the determination of Hypoxanthine (Hx), Inosine (HxR) and Inosine monophosphate (IMP). Calibration curves

  10. Quantification of allantoin, uric acid, xanthine and hypoxanthine in ovine urine by high-performance liquid chromatography and photodiode array detection

    Microsoft Academic Search

    M Czauderna; J Kowalczyk

    2000-01-01

    A HPLC method for the determination of allantoin, uric acid, hypoxanthine and xanthine (purine metabolites) in ovine urine without the disadvantages inherent in derivatization is described. After dilution 1:6 with water, urine samples were injected onto the column. Separation and quantification of purine metabolites was achieved using two Nova-Pak C18 columns (4 ?m, 250×4.6 mm, Waters). A binary gradient program

  11. Long-range ferromagnetic ordering in a 3D Cu(II)-tetracarboxylate framework assisted by an unprecedented bidentate ?2-O1,N4 hypoxanthine nucleobase.

    PubMed

    Yang, En-Cui; Liu, Zheng-Yu; Liu, Zhong-Yi; Zhao, Li-Na; Zhao, Xiao-Jun

    2010-10-14

    The first hypoxanthine (hypH)-assisted 3D Cu(II)-tetracarboxylate framework, {[Cu(2)(hypH)(0.5)(H(2)O)(0.5)(btec)]·1.5H(2)O}(n) (btec = 1,2,4,5-benzenetetracarboxylate), was synthesized and exhibits long-range ferromagnetic ordering below 4.5 K, which opens a new window for the applications of nucleobase-based MOFs as magnetic materials. PMID:20820623

  12. Detection of Wild-Type Hypoxanthine Guanine Phosphoribosyl Transferase of Lymphocytes in GammA-Irradiated Mice with Surface Plasmon Resonance

    Microsoft Academic Search

    Xiaohong Zhang; Zhichao Lou; Ailian Wang; Haiqian Zhang

    2012-01-01

    A quick and sensitive detection of the wild-type hypoxanthine guanine phosphoribosyl transferase (HPRT) was developed. HPRT is a biomarker for radiation exposure. The conventional HPRT measurement technique is to detect the mutant HPRT which is time-consuming and with low sensitivity. In this study, the wild-type HPRT was detected as a gamma radiation biomarker using a surface plasmon resonance (SPR) biosensor

  13. Metabolic engineering of the purine biosynthetic pathway in Corynebacterium glutamicum results in increased intracellular pool sizes of IMP and hypoxanthine

    PubMed Central

    2012-01-01

    Background Purine nucleotides exhibit various functions in cellular metabolism. Besides serving as building blocks for nucleic acid synthesis, they participate in signaling pathways and energy metabolism. Further, IMP and GMP represent industrially relevant biotechnological products used as flavor enhancing additives in food industry. Therefore, this work aimed towards the accumulation of IMP applying targeted genetic engineering of Corynebacterium glutamicum. Results Blocking of the degrading reactions towards AMP and GMP lead to a 45-fold increased intracellular IMP pool of 22 ?mol gCDW-1. Deletion of the pgi gene encoding glucose 6-phosphate isomerase in combination with the deactivated AMP and GMP generating reactions, however, resulted in significantly decreased IMP pools (13 ?mol gCDW-1). Targeted metabolite profiling of the purine biosynthetic pathway further revealed a metabolite shift towards the formation of the corresponding nucleobase hypoxanthine (102 ?mol gCDW-1) derived from IMP degradation. Conclusions The purine biosynthetic pathway is strongly interconnected with various parts of the central metabolism and therefore tightly controlled. However, deleting degrading reactions from IMP to AMP and GMP significantly increased intracellular IMP levels. Due to the complexity of this pathway further degradation from IMP to the corresponding nucleobase drastically increased suggesting additional targets for future strain optimization. PMID:23092390

  14. The role of human cytochrome P4503A4 in biotransformation of tissue-specific derivatives of 7H-dibenzo[c,g]carbazole

    SciTech Connect

    Mesarosova, Monika; Valovicova, Zuzana; Srancikova, Annamaria [Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, 833 91 Bratislava (Slovakia); Krajcovicova, Zdenka [Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, 833 91 Bratislava (Slovakia); Alexander Dubcek University of Trencin, Studentska 2, 911 01 Trencin (Slovakia); Milcova, Alena [Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 142 20 Prague 4 (Czech Republic); Sokolova, Romana [J. Heyrovsky Institute of Physical Chemistry, v.v.i., Academy of Sciences of the Czech Republic, Dolejskova 3, 18223 Prague (Czech Republic); Schmuczerova, Jana; Topinka, Jan [Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 142 20 Prague 4 (Czech Republic); Gabelova, Alena, E-mail: alena.gabelova@savba.sk [Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, 833 91 Bratislava (Slovakia)

    2011-09-15

    The environmental pollutant 7H-dibenzo[c,g]carbazole (DBC) and its derivative, 5,9-dimethylDBC (DiMeDBC), produced significant and dose-dependent levels of micronuclei followed by a substantial increase in the frequency of apoptotic cells in the V79MZh3A4 cell line stably expressing the human cytochrome P450 (hCYP) 3A4. In contrast, neither micronuclei nor apoptosis were found in cells exposed to the sarcomagenic carcinogen, N-methylDBC (N-MeDBC). A slight but significant level of gene mutations and DNA adducts detected in V79MZh3A4 cells treated with N-MeDBC, only at the highest concentration (30 {mu}M), revealed that this sarcomagenic carcinogen was also metabolized by hCYP3A4. Surprisingly, DBC increased the frequency of 6-thioguanine resistant (6-TG{sup r}) mutations only at the highest concentration (30 {mu}M), while DiMeDBC failed to increase the frequency of these mutations. The resistance to 6-thioguanine is caused by the mutations in the hypoxanthine-guanine phosphoribosyltransferase (Hprt) gene. The molecular analysis of the coding region of Hprt gene showed a deletion of the entire exon 8 in DiMeDBC-induced 6-TG{sup r} mutants, while no changes in the nucleotide sequences were identified in 6-TG{sup r} mutants produced by DBC and N-MeDBC. Based on our results, we suggest that hCYP3A4 is involved in the metabolism of DBC and its tissue-specific derivatives. While hCYP3A4 probably plays an important role in biotransformation of the liver carcinogens, DBC and DiMeDBC, it might only have a marginal function in N-MeDBC metabolism. - Highlights: > DBC activation via CYP3A4 resulted in micronuclei, DNA adduct formation and mutations in V79MZh3A4 cells. > The CYP3A4-mediated DiMeDBC activation caused micronuclei followed by apoptosis in V79MZh3A4 cells. > The genotoxic effects produced by N-MeDBC in V79MZh3A4 cells were negligible. > The hCYP3A4 may play an important role in DBC and DiMeDBC metabolism. > The CYP3A4 might only have a marginal function in N-MeDBC metabolism.

  15. Bilirubin UDP-glucuronosyltransferase 1A1 (UGT1A1) gene promoter polymorphisms and HPRT, glycophorin A, and micronuclei mutant frequencies in human blood.

    PubMed

    Grant, Delores J; Hall, Ingrid J; Eastmond, David A; Jones, Irene M; Bell, Douglas A

    2004-05-01

    A dinucleotide repeat polymorphism (5-, 6-, 7-, or 8-TA units) has been identified within the promoter region of UDP-glucuronosyltransferase 1A1 (UGT1A1) gene. The 7-TA repeat allele has been associated with elevated serum bilirubin levels that cause a mild hyperbilirubinemia (Gilbert's syndrome). Studies suggest that promoter transcriptional activity of UGT1A1 is inversely related to the number of TA repeats, and that unconjugated bilirubin concentration increases directly with the number of TA repeat elements. Because bilirubin is a known antioxidant, we hypothesized that UGT1A1 repeats associated with higher bilirubin may be protective against oxidative damage. We examined the effect of UGT1A1 genotype on somatic mutant frequency in the hypoxanthine-guanine phosphoribosyl-transferase (HPRT) gene in human lymphocytes and the glycophorin A (GPA) gene of red blood cells (both N0, NN mutants), and the frequency of lymphocyte micronuclei (both kinetochore (K)-positive or micronuclei K-negative) in 101 healthy smoking and nonsmoking individuals. As hypothesized, genotypes containing 7- and 8-TA displayed marginally lower GPA_NN mutant frequency relative to 5/5, 5/6, 6/6 genotypes ( [Formula: see text] ). In contrast, our analysis showed that lower expressing UGT1A1 alleles (7- and 8-TA) were associated with modestly increased HPRT mutation frequency ( [Formula: see text] ), while the same low-expression genotypes were not significantly associated with micronuclei frequencies (K-positive or K-negative) when compared to high-expression genotypes (5- and 6-TA). We found weak evidence that UGT1A1 genotypes containing 7- and 8-TA were associated with increased GPA_NØ mutant frequency relative to 5/5, 5/6, 6/6 genotypes ( [Formula: see text] ). These data suggest that UGT1A1 genotype may modulate somatic mutation of some types, in some cell lineages, by a mechanism not involving bilirubin antioxidant activity. More detailed studies examining UGT1A1 promoter variation, oxidant/antioxidant balance and genetic damage will be needed. PMID:15099818

  16. Biochemical Characterization of Quinolinic Acid Phosphoribosyltransferase from Mycobacterium tuberculosis H37Rv and Inhibition of Its Activity by Pyrazinamide

    PubMed Central

    Kim, Hyun; Shibayama, Keigo; Rimbara, Emiko; Mori, Shigetarou

    2014-01-01

    Quinolinic acid phosphoribosyltransferase (QAPRTase, EC 2.4.2.19) is a key enzyme in the de novo pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis and a target for the development of new anti-tuberculosis drugs. QAPRTase catalyzes the synthesis of nicotinic acid mononucleotide from quinolinic acid (QA) and 5-phosphoribosyl-1-pyrophosphate (PRPP) through a phosphoribosyl transfer reaction followed by decarboxylation. The crystal structure of QAPRTase from Mycobacterium tuberculosis H37Rv (MtQAPRTase) has been determined; however, a detailed functional analysis of MtQAPRTase has not been published. Here, we analyzed the enzymatic activities of MtQAPRTase and determined the effect on catalysis of the anti-tuberculosis drug pyrazinamide (PZA). The optimum temperature and pH for MtQAPRTase activity were 60°C and pH 9.2. MtQAPRTase required bivalent metal ions and its activity was highest in the presence of Mg2+. Kinetic analyses revealed that the Km values for QA and PRPP were 0.08 and 0.39 mM, respectively, and the kcat values for QA and PRPP were 0.12 and 0.14 [s-1], respectively. When the amino acid residues of MtQAPRTase, which may interact with QA, were substituted with alanine residues, catalytic activity was undetectable. Further, PZA, which is an anti-tuberculosis drug and a structural analog of QA, markedly inhibited the catalytic activity of MtQAPRTase. The structure of PZA may provide the basis for the design of new inhibitors of MtQAPRTase. These findings provide new insights into the catalytic properties of MtQAPRTase. PMID:24949952

  17. Interactions at the 2 and 5 positions of 5-phosphoribosyl pyrophosphate are essential in Salmonella typhimurium quinolinate phosphoribosyltransferase†

    PubMed Central

    Bello, Zainab; Stitt, Barbara; Grubmeyer, Charles

    2010-01-01

    Quinolinate phosphoribosyltransferase (QAPRTase, EC 2.4.2.19) catalyzes an unusual phosphoribosyl transfer that is linked to a decarboxylation reaction to form the NAD precursor nicotinate mononucleotide, carbon dioxide, and pyrophosphate from quinolinic acid (QA) and 5-phosphoribosyl 1-pyrophosphate (PRPP). Structural studies and sequence similarities with other PRTases have implicated Glu214, Asp235, Lys153 and Lys284 in contributing to catalysis through direct interaction with PRPP. The four residues were substituted by site-directed mutagenesis. A nadC deletant form of BL21DE3 was created to eliminate trace contamination by chromosomal QAPRTase. The mutant enzymes were readily purified and retained their dimeric aggregation state on gel filtration. Substitution of Lys153 with Ala resulted in an inactive enzyme, indicating its essential nature. Mutation of Glu214 to Ala or Asp caused at least a 4000-fold reduction in kcat, with 10-fold increases in Km and KD values for PRPP. However, mutation of Glu214 to Gln had only modest effects on ligand binding and catalysis. pH profiles indicated that the deprotonated form of a residue with pKa of 6.9 is essential for catalysis. The WT-like pH-profile of the E214Q mutant indicated that Glu214 is not that residue. Mutation of Asp235 to Ala did not affect ligand binding or catalysis. Mutation of Lys284 to Ala decreased kcat by 30-fold and increased Km and KD values for PRPP by 80-fold and at least 20-fold, respectively. The study suggests that Lys153 is necessary for catalysis and important for PRPP binding, Glu214 provides a hydrogen bond necessary for catalysis but does not act as a base or electrostatically to stabilize the transition state, Lys284 is involved in PRPP binding and Asp235 is not essential. PMID:20047307

  18. Non-invasive molecular and functional imaging of cytosine deaminase and uracil phosphoribosyltransferase fused with red fluorescence protein

    PubMed Central

    XING, LIGANG; DENG, XUELONG; KOTEDIA, KHUSHALI; ACKERSTAFF, ELLEN; PONOMAREV, VLADIMIR; LING, C. CLIFTON; KOUTCHER, JASON A.; LI, GLORIA C.

    2014-01-01

    Introduction Increased expression of cytosine deaminase (CD) and uracil phosphoribosyltransferase (UPRT) may improve the antitumoral effect of 5-fluorouracil (5-FU) and 5-fluorocytosine (5-FC), and thereby enhance the potential of gene-directed enzyme prodrug therapy. For the applicability of gene-directed enzyme prodrug therapy in a clinical setting, it is essential to be able to monitor the transgene expression and function in vivo. Thus, we developed a preclinical tumor model to investigate the feasibility of using magnetic resonance spectroscopy and optical imaging to measure non-invasively CD and UPRT expression and function. Materials and methods Expression vectors of CD or CD/UPRT fused to monomeric DsRed (mDsRed) were constructed and rat prostate carcinoma (R3327-AT) cell lines stably expressing either CD/mDsRed or CD/UPRT/mDsRed were generated. The expression of the fusion proteins was evaluated by flow cytometry, fluorescence microscopy, and Western blot analysis. The function of the fusion protein was confirmed in vitro by assessing 5-FC and 5-FU cytotoxicity. In vivo fluorine-19 magnetic resonance spectroscopy (19F MRS) was used to monitor the conversion of 5-FC to 5-FU in mice bearing the R3327-CD/mDsRed and R3327-CD/UPRT/mDsRed tumor xenografts. Results Sensitivity to 5-FC and 5-FU was higher in cells stably expressing the CD/UPRT/mDsRed fusion gene than in cells stably expressing CD/mDsRed alone or wild-type cells. Whole tumor 19F MRS measurements showed rapid conversion of 5-FC to 5-FU within 20 min after 5-FC was administered intravenously in both CD/mDsRed and CD/UPRT/mDsRed tumors with subsequent anabolism to cytotoxic fluoronucleotides (FNucs). CD/UPRT/mDsRed tumor was more efficient in these processes. Conclusion This study demonstrates the utility of these tumor models stably expressing CD or CD/UPRT to non-invasively evaluate the efficacy of the transgene expression/activity by monitoring drug metabolism in vivo using MRS, with potential applications in preclinical and clinical settings. PMID:18661431

  19. DNA fragmentation, dATP pool elevation and potentiation of antifolate cytotoxicity in L1210 cells by hypoxanthine.

    PubMed Central

    Kwok, J. B.; Tattersall, M. H.

    1992-01-01

    Exogenous purines (greater than or equal to 10(-5)M) can modulate the cytotoxicity of methotrexate (MTX) in cultured cells, protecting cells at low MTX concentrations (less than or equal to 8 x 10(-8) M) and markedly potentiating its effect at higher concentrations. The ability of hypoxanthine (HX) to modulate the effects of two antifolates-ICI 198583 (an inhibitor of thymidylate synthetase) and piritrexim (PTX, a lipophilic inhibitor of DHFR)-was investigated using cultured mouse leukaemic cells, L1210. HX (10(-4) M) was found to potentiate only the cytotoxicity of DHFR inhibitors (MTS and PTX), increasing cell kill by 20-70 fold to the level achieved by an equivalent concentration (10(-5) M) of ICI 198583 alone. Agarose gel electrophoresis of DNA extracted from cells exposed to antifolates for 24 h demonstrated that the chromatin was cleaved into multimers of 200 base pairs. This pattern of DNA cleavage indicates cell death via apoptosis. The degree of DNA fragmentation was found to be closely linked to cytotoxicity. DNA fragmentation increased from 50% in cells treated with 10(-5) M MTX or PTX to 70% when HX was added with the drugs, a level achieved by 10(-5)M ICI 198583 alone. HX potentiation of cytotoxicity was correlated with a substantial increase in dATP in conjunction with low dTTP pools. The specific potentiation of DHFR inhibitors by HX may be due to their inhibition of purine synthesis with a concurrent rise in PRPP levels. Addition of HX with MTX substantially raised intracellular purine levels via the salvage pathway as indicated by ribonucleotide pool measurements. ICI 198583, on the other hand, stimulated de novo purine synthesis with or without added HX. Treatment with MTX plus HX or ICI 198583 (with or without HX) caused a reduction of dTTP pools to 8% of untreated control and excess dATP accumulation. The subsequent elevation (to 300% of control) of the dATP pool may provide a signal for endonucleolytic fragmentation of DNA and subsequent cell death. Images Figure 3 PMID:1562458

  20. Evidence for redox cycling of lawsone (2-hydroxy-1,4-naphthoquinone) in the presence of the hypoxanthine/xanthine oxidase system.

    PubMed

    Osman, A M; van Noort, P C M

    2003-01-01

    This study reports that lawsone (2-hydroxy-1,4-naphthoquinone) undergoes redox cycling in the presence of the hypoxanthine/xanthine oxidase system. The rate of cytochrome c reduction obtained in the presence of 80 microM lawsone was almost three times the rate of cytochrome c reduction measured in its absence. This increase in the rate of cytochrome c reduction was partially inhibited by superoxide dismutase, suggesting the involvement of O(2)(.-) in this process. It is remarkable to note that, even though lawsone is considered to be a non-redox-cycling quinone in vitro, this quinone was shown to be more toxic in vivo in rats than menadione, causing haemolytic anemia of an oxidative nature and renal damage. The view that this quinone is a non-redox-cycling quinone was based on the inability of one-electron-transferring flavoenzymes such as NADPH-cytochrome c reductase to reduce this naphthoquinone. Our finding that lawsone, like menadione, undergoes redox cycling in the presence of the hypoxanthine/xanthine oxidase system could explain the observed oxidative damage of tissues inflicted by this quinone in rats in vivo. Such an observation therefore reconciles the in vivo toxicity results of this naphthoquinone with those of in vitro experiments. PMID:12884402

  1. Adenine Phosphoribosyltransferase (APRT) Deficiency

    MedlinePLUS

    ... reddish-brown diaper stains. The 2,8-dihydroxyadenine crystals should be easily detected by urine microscopy. The ... enzyme activity. Furthermore, analysis of 2,8-DHA crystals and stone material may confirm the diagnosis. What ...

  2. Transport of [ 14C]hypoxanthine by sheep choroid plexus epithelium as a monolayer in primary culture: Na +-dependent and Na +-independent uptake by the apical membrane and rapid intracellular metabolic conversion to nucleotides

    Microsoft Academic Search

    Aleksandra J. Isakovic; Sonja Misirlic Dencic; Malcolm B. Segal; Zoran B. Redzic

    2008-01-01

    Hypoxanthine is the main product of purine metabolic degradation and previous studies have revealed that it is present in the sheep CSF and plasma in micromolar concentrations. The aim of this study was to elucidate the transport of this molecule across the sheep choroid plexus epithelium (CPE) as a monolayer in primary culture, to explore the mechanism of uptake by

  3. DNA damage and mutation in human cells exposed to nitric oxide in vitro.

    PubMed Central

    Nguyen, T; Brunson, D; Crespi, C L; Penman, B W; Wishnok, J S; Tannenbaum, S R

    1992-01-01

    Nitric oxide (NO.) is a physiological messenger formed by several cell types. Reaction with O2 forms oxides that nitrosate amines at pH values near 7. We now report experiments in which NO. was added to intact human cells and to aerobic solutions of DNA, RNA, guanine, or adenine. TK6 human lymphoblastoid cells were mutated 15- to 18-fold above background levels at both the HPRT and TK gene loci. Xanthine and hypoxanthine, from deamination of guanine and adenine, respectively, were formed in all cases. NO. induced dose-responsive DNA strand breakage. Yields of xanthine ranged from nearly equal to about 80-fold higher than those of hypoxanthine. Yields of xanthine and hypoxanthine from nucleic acids were higher than those from free guanine and adenine. This was most pronounced for xanthine; 0.3 nmol/mg was formed from free guanine vs. 550 nmol/mg from calf thymus RNA. Nitric oxide added to TK6 cells produced a 40- to 50-fold increase in hypoxanthine and xanthine in cellular DNA. We believe that these results, plus the expected deaminations of cytosine to uracil and 5-methylcytosine to thymine, account for the mutagenicity of nitric oxide toward bacteria and mammalian cells. Images PMID:1557408

  4. Human somatic mutation assays as biomarkers of carcinogenesis

    SciTech Connect

    Compton, P.J.E.; Smith, M.T. (Univ. of California, Berkeley (United States)); Hooper, K. (California Dept. of Health Services, Berkeley (United States))

    1991-08-01

    This paper describes four assays that detect somatic gene mutations in humans: the hypoxanthine-guanine phosphoribosyl transferase assay, the glycophorin A assay, the HLA-A assay, and the sickle cell hemoglobin assay. Somatic gene mutations can be considered a biomarker of carcinogenesis, and assays for somatic mutation may assist epidemiologists in studies that attempt to identify factors associated with increased risks of cancer. Practical aspects of the use of these assays are discussed.

  5. Molecular analyses of in vivo hprt mutations in human T-lymphocytes: IV. Studies in newborns

    SciTech Connect

    McGinniss, M.J.; Nicklas, J.A.; Albertini, R.J. (Univ. of Vermont, Burlington (USA))

    1989-01-01

    In order to characterize in vivo gene mutations that occur during fetal development, molecular analyses were undertaken of mutant 6-thioguanine resistant T-lymphocytes isolated from placental cord blood samples of 13 normal male newborns. These mutant T-cells were studied to define hypoxanthine-guanine phosphoribosyltransferase (hprt) gene structural alterations and to determine T-cell receptor (TCR) gene rearrangement patterns. Structural hprt alterations, as shown by Southern blot analyses, occurred in 85% of these mutant clones. These alterations consisted mostly of deletion of exons 2 and 3. These findings contrast with the 10-20% of gross structural alterations occurring randomly across the entire gene previously reported for T-cell mutants isolated from normal young adults. Iterative analyses of hprt structural alterations and TCR gene rearrangement patterns show that approximately one-third of the newborn derived mutants may have originated as pre- or intrathymic hprt mutations. This too contrasts with previous findings in adults where the background in vivo hprt mutations appeared to originate in postthymic T-lymphocytes.

  6. High-frequency structural gene deletion as the basis for functional hemizygosity of the adenine phosphoribosyltransferase locus in Chinese hamster ovary cells.

    PubMed Central

    Adair, G M; Stallings, R L; Nairn, R S; Siciliano, M J

    1983-01-01

    The CHO-AT3-2 Chinese hamster ovary cell line is functionally hemizygous for the adenine phosphoribosyltransferase (APRT; EC 2.4.2.7) locus. Class 1 APRT +/- heterozygotes, such as CHO-AT3-2, can be isolated at high spontaneous frequencies from wild-type CHO cell populations. Simon et al. [Simon, A. E., Taylor, M. W., Bradley, W. E. C. & Thompson, L. (1982) Mol. Cell. Biol. 2, 1126-1133] have proposed that a high-frequency event that inactivates one APRT allele might be responsible for both the spontaneous generation of class 1 APRT +/- heterozygotes and the high-frequency occurrence of APRT- mutants in class 2 APRT +/- heterozygote populations. This event appears to occur at only one of the two APRT alleles. To investigate the nature of this high-frequency event, and to determine the genetic basis for functional hemizygosity of the APRT locus in CHO-AT3-2 cells, we have mapped the APRT locus by using CHO-AT3-2-mouse somatic cell hybrids. Our data confirm that CHO-AT3-2 cells have a single functional APRT allele, which is located on the Z7 chromosome. Karyotypic analysis of CHO-AT3-2 revealed an interstitial deletion on the long arm of the Z4 chromosome, in the very region where the other APRT allele should be located. To determine whether the Z4q interstitial deletion had resulted in physical loss of the APRT gene, DNA from CHO-AT3-2-mouse cell hybrids that had either lost or retained the Z4q- chromosome was analyzed for the presence of CHO APRT coding sequences. Our data suggest that allele-specific high-frequency structural gene deletion events involving the long arm of chromosome Z4 are responsible for the spontaneous generation of functional hemizygosity at the APRT locus in CHO cells. Images PMID:6310607

  7. Quantitative assay for mutation in diploid human lymphoblasts using microtiter plates

    SciTech Connect

    Furth, E.A.; Thilly, W.G.; Penman, B.W.; Liber, H.L.; Rand, W.M.

    1981-01-01

    A microtiter plating technique which eliminates the need for soft agar and fibroblast feeder layers to determine the colony-forming ability of diploid human lymphoblast lines was described. The calculation of cloning efficiency is based on the Poisson distribution, and a statistical method for calculating confidence intervals is presented. This technique has been applied to the comcomitant examination of induced mutation at the putative loci for hypoxanthine guanine phosphoribosyl transferase, thymidine, kinase, and Na/sup +//K/sup +/ adenosine triphosphatase.

  8. The human ?-amyloid precursor protein: biomolecular and epigenetic aspects.

    PubMed

    Nguyen, Khue Vu

    2015-03-01

    Beta-amyloid precursor protein (APP) is a membrane-spanning protein with a large extracellular domain and a much smaller intracellular domain. APP plays a central role in Alzheimer's disease (AD) pathogenesis: APP processing generates ?-amyloid (A?) peptides, which are deposited as amyloid plaques in the brains of AD individuals; point mutations and duplications of APP are causal for a subset of early-onset familial AD (FAD) (onset age <65 years old). However, these mutations in FAD represent a very small percentage of cases (?1%). Approximately 99% of AD cases are nonfamilial and late-onset, i.e., sporadic AD (SAD) (onset age >65 years old), and the pathophysiology of this disorder is not yet fully understood. APP is an extremely complex molecule that may be functionally important in its full-length configuration, as well as the source of numerous fragments with varying effects on neural function, yet the normal function of APP remains largely unknown. This article provides an overview of our current understanding of APP, including its structure, expression patterns, proteolytic processing and putative functions. Importantly, and for the first time, my recent data concerning its epigenetic regulation, especially in alternative APP pre-mRNA splicing and in the control of genomic rearrangements of the APP gene, are also reported. These findings may provide new directions for investigating the role of APP in neuropathology associated with a deficiency in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt) found in patients with Lesch-Nyhan syndrome (LNS) and its attenuated variants (LNVs). Also, these findings may be of significance for research in neurodevelopmental and neurodegenerative disorders in which the APP gene is involved in the pathogenesis of diseases such as autism, fragile X syndrome (FXS) and AD, with its diversity and complexity, SAD in particular. Accurate quantification of various APP-mRNA isoforms in brain tissues is needed, and antisense drugs are potential treatments. PMID:25719338

  9. The relationship of visfatin/pre-B-cell colony-enhancing factor/nicotinamide phosphoribosyltransferase in adipose tissue with inflammation, insulin resistance, and plasma lipids.

    PubMed

    Chang, Yi-Cheng; Chang, Tien-Jyun; Lee, Wei-Jei; Chuang, Lee-Ming

    2010-01-01

    Visfatin/pre-B-cell colony-enhancing factor (PBEF)/nicotinamide phosphoribosyltransferase (Nampt) has been proposed as an insulin-mimicking adipocytokine predominantly secreted from visceral adipose tissue (VAT) and correlated with obesity. However, recent evidence challenged this proposal and instead suggested visfatin/PBEF/Nampt as a proinflammatory cytokine. The study aimed to examine whether visfatin/PBEF/Nampt was predominantly expressed in VAT and was correlated with obesity. The relationship of visfatin/PBEF/Nampt gene expression in adipose tissues with proinflammatory gene expression and metabolic phenotypes was also examined. The relative messenger RNA (mRNA) levels of visfatin/PBEF/Nampt, macrophage-specific marker CD68, and proinflammatory genes were measured in paired abdominal VAT and subcutaneous adipose tissues (SAT) and from 53 nondiabetic adults using quantitative real-time polymerase chain reaction. Fasting glucose, insulin, triglyceride, cholesterol, and uric acid levels were measured; and systemic insulin sensitivity was quantified with modified insulin suppression tests. There was no difference in visfatin/PBEF/Nampt mRNA levels between VAT and SAT, and neither was associated with measures of obesity. Visfatin/PBEF/Nampt mRNA levels were strongly correlated with proinflammatory gene expression including CD68 and tumor necrosis factor-alpha gene in both VAT and SAT. The VAT and SAT visfatin/PBEF/Nampt mRNA expressions were positively correlated with steady-state plasma glucose concentrations measured with modified insulin suppression tests, a direct measurement of systemic insulin resistance (r = 0.42, P = .03 and r = 0.44, P = .03, respectively). The VAT visfatin/PBEF/Nampt mRNA expression was also positively correlated with fasting triglyceride (r = 0.42, P = .002) and total cholesterol levels (r = 0.37, P = .009). Visfatin/PBEF/Nampt is not predominantly secreted from VAT and is not correlated with obesity. Our findings suggest that visfatin/PBEF/Nampt is a proinflammatory marker of adipose tissue associated with systemic insulin resistance and hyperlipidemia. PMID:19765775

  10. Functional Identification of the Hypoxanthine/Guanine Transporters YjcD and YgfQ and the Adenine Transporters PurP and YicO of Escherichia coli K-12*

    PubMed Central

    Papakostas, Konstantinos; Botou, Maria; Frillingos, Stathis

    2013-01-01

    The evolutionarily broad family nucleobase-cation symporter-2 (NCS2) encompasses transporters that are conserved in binding site architecture but diverse in substrate selectivity. Putative purine transporters of this family fall into one of two homology clusters: COG2233, represented by well studied xanthine and/or uric acid permeases, and COG2252, consisting of transporters for adenine, guanine, and/or hypoxanthine that remain unknown with respect to structure-function relationships. We analyzed the COG2252 genes of Escherichia coli K-12 with homology modeling, functional overexpression, and mutagenesis and showed that they encode high affinity permeases for the uptake of adenine (PurP and YicO) or guanine and hypoxanthine (YjcD and YgfQ). The two pairs of paralogs differ clearly in their substrate and ligand preferences. Of 25 putative inhibitors tested, PurP and YicO recognize with low micromolar affinity N6-benzoyladenine, 2,6-diaminopurine, and purine, whereas YjcD and YgfQ recognize 1-methylguanine, 8-azaguanine, 6-thioguanine, and 6-mercaptopurine and do not recognize any of the PurP ligands. Furthermore, the permeases PurP and YjcD were subjected to site-directed mutagenesis at highly conserved sites of transmembrane segments 1, 3, 8, 9, and 10, which have been studied also in COG2233 homologs. Residues irreplaceable for uptake activity or crucial for substrate selectivity were found at positions occupied by similar role amino acids in the Escherichia coli xanthine- and uric acid-transporting homologs (XanQ and UacT, respectively) and predicted to be at or around the binding site. Our results support the contention that the distantly related transporters of COG2233 and COG2252 use topologically similar side chain determinants to dictate their function and the distinct purine selectivity profiles. PMID:24214977

  11. [Molecular cloning and expression analysis of swamp eel (Monopterus albus) Hprt].

    PubMed

    He, Yan; Shang, Xuan; Cheng, Han-Hua; Zhou, Rong-Jia

    2006-06-01

    The enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) plays an important role in the purine salvage pathways. Full-length cDNA of swamp eel (Monopterus albus, the rice field eel) Hprt gene was obtained by the RACE method. The cDNA sequence was 1452 bp in length, which encoded a protein of 218 amino acids. Amino acid identities of Hprt between swamp eel and other vertebrates including human, mouse, chicken and zebrafish were more than 76.7%. Phylogenetic tree analysis based on the amino acid sequences showed that Hprt of swamp eel and zebrafish was in one clade. RT-PCR analysis showed ubiquitous expression pattern of swamp eel Hprt in adult tissues, suggesting that it has a constitutive function and is conserved during evolution. PMID:16818429

  12. A characteristic of mutants induced by the oncogene c-Ha-ras1 and the nature of the mutagenic effect of the oncogene

    SciTech Connect

    Bobrysheva, I.V.; Varshaver, N.B. [Inst. of Molecular Genetics, Moscow (Russian Federation)

    1995-12-01

    Chinese hamster cell clones of independent origin, which were resistant to purine base analogs and induced by the activated c-Ha-ras1 oncogene, were isolated. It was shown that the isolated clones stably retained resistance after cultivation on a medium without an analogy, confirming the mutational nature of the resistance. Most of the clones are able to grow on the HAT medium, retaining partial activity of the hypoxanthine phosphoribosyltransferase enzyme (HPRT); i.e., they are leaky mutants. Analysis by blot-hybridization did not reveal the presence of human ras-sequences in any of the mutants studied. Evidently, the mutagenic action of the oncogene is not insertional, and resistance is not linked to the stably integrated oncogene. The mutagenic effect of c-Ha-ras1 is likely to be of the {open_quotes}hit-and-run{close_quotes} type. 25 refs., 1 fig., 2 tabs.

  13. Genotoxic effects of sunlight-activated waste water in cultured mammalian cells.

    PubMed

    Strniste, G F; Chen, D J; Okinaka, R T

    1982-07-01

    Cultured Chinese hamster ovary cells were incubated with dilutions of an oil shale retort process water and exposed to nautral sunlight. An enhancement of sevenfold to ninefold was seen in photoinduced cytotoxicity (by a colony-forming assay) and mutagenicity [at the hypoxanthine phosphoribosyltransferase (HPRT) locus] for cells pretreated with the process water compared to effects seen in cells exposed to sunlight only. Significant photoinduced cytotoxicity was also observed in cultured human skin fibroblasts when exposed to the process water before being exposed to near UV (NUV) radiation. The mutation frequencies (determined for the HPRT locus) induced by the process water and NUV radiation were as great as those frequencies seen for far UV light alone. Increases in genotoxicity were observed in excision repair-deficient xeroderma pigmentosum skin fibroblasts when compared to the responses seen in normal cells. Risks to health resulting from the phototransformation of these oil shale retort process waste waters are unassessed at this time. PMID:6954312

  14. Attenuated Variants of Lesch-Nyhan Disease

    ERIC Educational Resources Information Center

    Jinnah, H. A.; Ceballos-Picot, Irene; Torres, Rosa J.; Visser, Jasper E.; Schretlen, David J.; Verdu, Alfonso; Larovere, Laura E.; Chen, Chung-Jen; Cossu, Antonello; Wu, Chien-Hui; Sampat, Radhika; Chang, Shun-Jen; de Kremer, Raquel Dodelson; Nyhan, William; Harris, James C.; Reich, Stephen G.; Puig, Juan G.

    2010-01-01

    Lesch-Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the…

  15. Involvement of endoplasmic reticulum stress in -cell apoptosis: a proteomic approach in INS-1E cells.

    E-print Network

    #12;Abbreviations: ATF6: activating transcription factor 6 CHOP: CCAAT/enhancer binding protein CPA complete protein translation shut-down, indicating a higher sensitivity of INS-1E cells to CPA- induced ER ribonucleoprotein K HPRT: hypoxanthine-guanine phosphoribosyltransferase HSPA5: 78 kDa glucose-regulated protein

  16. MULTIPLE-ENDPOINT MUTAGENESIS WITH CHINESE HAMSTER OVARY (CHO) CELLS: EVALUATION WITH EIGHT CARCINOGENIC AND NON-CARCINOGENIC COMPOUNDS

    EPA Science Inventory

    Using Chinese hamster ovary (CHO) cells in culture, the authors have defined an assay, CHO/HGPRT, to quantify mutagen-induced cytotoxicity and mutations at the hypoxanthine-guanine phosphoribosyltransferase (hgprt) locus. This assay permits elucidation of the structure-activity r...

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

    SciTech Connect

    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.

  18. Multiple dispersed spontaneous mutations: a novel pathway of mutation in a malignant human cell line.

    PubMed Central

    Harwood, J; Tachibana, A; Meuth, M

    1991-01-01

    We analyzed the nature of spontaneous mutations at the autosomal locus coding for adenine phosphoribosyltransferase in the human colorectal carcinoma cell line SW620 to establish whether distinctive mutational pathways exist that might underlie the more complex genome rearrangements arising in tumor cells. Point mutations occur at a low rate in aprt hemizygotes derived from SW620, largely as a result of base substitutions at G.C base pairs to yield transversions and transitions. However, a novel pathway is evident in the form of multiple dispersed mutations in which two errors, separated by as much as 1,800 bp, fall in the same mutant gene. Such mutations could be the result of error-prone DNA synthesis occurring during normal replication or during long-patch excision-repair of spontaneously arising DNA lesions. This process could also contribute to the chromosomal instability evident in these tumor cells. Images PMID:2038324

  19. Local bystander effect induces dormancy in human medullary thyroid carcinoma model in vivo.

    PubMed

    Kucerova, Lucia; Feketeova, Lucia; Matuskova, Miroslava; Kozovska, Zuzana; Janega, Pavol; Babal, Pavel; Poturnajova, Martina

    2013-07-28

    The extent of local bystander effect induced by fusion yeast cytosine deaminase::uracil phosphoribosyltransferase (yCD) in combination with 5-fluorocytosine (5FC) was evaluated in xenogeneic model of human medullary thyroid carcinoma (MTC). This approach to gene-directed enzyme/prodrug therapy (GDEPT) induces strong bystander cytotoxicity. Effector yCD-TT mixed with target EGFP-TT cells in a ratio 2:9 could achieve significant tumor regression and 14-fold decrease in serum marker calcitonin upon 5FC administration. Histopathological analysis unraveled that antitumor effect resulted in tumor dormancy and proliferation arrest of remaining tumor cell clusters in vivo. yCD/5FC combination represents another GDEPT approach to achieve tumor growth control in MTC. PMID:23485727

  20. Gene duplication and inactivation in the HPRT gene family

    Microsoft Academic Search

    Alaine C. Keebaugh; Robert T. Sullivan; James W. Thomas

    2007-01-01

    Hypoxanthine phosphoribosyltransferase (HPRT1) is a key enzyme in the purine salvage pathway, and mutations in HPRT1 cause Lesch–Nyhan disease. The studies described here utilized targeted comparative mapping and sequencing, in conjunction with database searches, to assemble a collection of 53 HPRT1 homologs from 28 vertebrates. Phylogenetic analysis of these homologs revealed that the HPRT gene family expanded as the result

  1. Inactivation of the Mouse HPRTLocus by a 203-bp Retroposon Insertion and a 55-kb Gene-Targeted Deletion: Establishment of New HPRT-Deficient Mouse Embryonic Stem Cell Lines

    Microsoft Academic Search

    Hirohisa Tsuda; Catherine E. Maynard-Currie; Laura H. Reid; Takayuki Yoshida; Koji Edamura; Nobuyo Maeda; Oliver Smithies; Aya Jakobovits

    1997-01-01

    To obtain useful hypoxanthine phosphoribosyltransferase (HPRT)-deficient mouse ES cell lines, two different methods were employed: (i) selection of spontaneous 6-TG-resistant mutants and (ii) gene targeting of theHPRTlocus. The first approach resulted in the establishment of E14.1TG3B1, a spontaneous HPRT-deficient cell line with an insertional mutation of 203 bp in the third exon of theHPRTgene. The insert is highly homologous to

  2. Molecular Structure of 6-Mercaptopurine

    NSDL National Science Digital Library

    2002-09-12

    Gertrude B. Elion invented 6-mercaptopurine (6MP) in 1954 as a leukemia-fighting drug while she was working on antagonists of nucleic acid building blocks. 6MP is converted to thioinosinic acid by the enzyme hypoxanthine-guanine phosphoribosyltransferase, thus inhibiting RNA synthesis. Mercaptopurine is a drug that is used to treat certain types of cancer and leukemia. There are many side effects to this drug such as reduction of bone marrow, liver function, ulcers, and diarrhea.

  3. A sex-linked enzyme in birds-Z-chromosome conservation but no dosage compensation

    Microsoft Academic Search

    P. R. Baverstock; M. Adams; R. W. Polkinghorne; M. Gelder

    1982-01-01

    In birds, the female is the heterogametic sex and the sex-determining system is referred to as ZZ\\/ZW. In mammals the male is heterogametic, and the sex-determining system is referred to as XX\\/XY. The mammalian X chromosome appears to have been conserved largely intact during evolution. Thus the structural gene loci for glucose-6-phosphate de-hydrogenase, phosphoglycerate kinase, alpha-galactosidase and hypoxanthine-guanine phosphoribosyltransferase are

  4. Skeletal muscle NAMPT is induced by exercise in humans

    PubMed Central

    Costford, Sheila R.; Bajpeyi, Sudip; Pasarica, Magdalena; Albarado, Diana C.; Thomas, Shantele C.; Xie, Hui; Church, Timothy S.; Jubrias, Sharon A.; Conley, Kevin E.

    2010-01-01

    In mammals, nicotinamide phosphoribosyltransferase (NAMPT) is responsible for the first and rate-limiting step in the conversion of nicotinamide to nicotinamide adenine dinucleotide (NAD+). NAD+ is an obligate cosubstrate for mammalian sirtuin-1 (SIRT1), a deacetylase that activates peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?), which in turn can activate mitochondrial biogenesis. Given that mitochondrial biogenesis is activated by exercise, we hypothesized that exercise would increase NAMPT expression, as a potential mechanism leading to increased mitochondrial content in muscle. A cross-sectional analysis of human subjects showed that athletes had about a twofold higher skeletal muscle NAMPT protein expression compared with sedentary obese, nonobese, and type 2 diabetic subjects (P < 0.05). NAMPT protein correlated with mitochondrial content as estimated by complex III protein content (R2 = 0.28, P < 0.01), MRS-measured maximal ATP synthesis (R2 = 0.37, P = 0.002), and V?o2max (R2 = 0.63, P < 0.0001). In an exercise intervention study, NAMPT protein increased by 127% in sedentary nonobese subjects after 3 wk of exercise training (P < 0.01). Treatment of primary human myotubes with forskolin, a cAMP signaling pathway activator, resulted in an ?2.5-fold increase in NAMPT protein expression, whereas treatment with ionomycin had no effect. Activation of AMPK via AICAR resulted in an ?3.4-fold increase in NAMPT mRNA (P < 0.05) as well as modest increases in NAMPT protein (P < 0.05) and mitochondrial content (P < 0.05). These results demonstrate that exercise increases skeletal muscle NAMPT expression and that NAMPT correlates with mitochondrial content. Further studies are necessary to elucidate the pathways regulating NAMPT as well as its downstream effects. PMID:19887595

  5. Characterization of a human antigen specific helper factor

    SciTech Connect

    Richardson, B.

    1986-03-01

    While antigen (Ag) specific helper factors have been characterized in mice, similar molecules have not been identified in humans. To characterize human antigen specific helper molecules, an IL-2 dependent tetanus toxoid (T.T.) reactive T cell line was fused with a 6-thioguanine resistant CEM line, and hybrids selected in medium containing hypoxanthine and azaserine. Hybrids were screened by culturing the cells with /sup 35/S-Met then reacting the supernatants with T.T. or hepatitis vaccine immobilized on nitrocellulose. One hybrid, TT6BA-O, was identified which secreted a Met-containing molecule which bound T.T. but not hepatitis vaccine. Supernatants from TT6BA-O, but not the parent CEM line, when added to autologous peripheral blood mononuclear cells (PBMC's) stimulated secretion of T.T. specific antibodies (Abs). Specificity controls demonstrated that TT6BA-O supernatant did not induce antibodies to diphtheria toxoid, hepatitis vaccine or pneumococcal polysaccharide, and total immunoglobulin (lg) synthesis was minimally increased. In contrast, pokeweed mitogen stimulated significant lg synthesis as well as Ab's to pneumococcal polysaccharide and T.T. TT6BA-O supernatant induced anti-T.T.Ab's in autologous PBMC's but not PBMC's from 3 unrelated donors, suggesting that the activity of the helper factor is restricted, possibly by the MHC. The molecular weight of the helper factor was estimated at 100,000-150,000 by Sephacryl S-300 chromatography. Finally, the helper factor could be demonstrated to bind and elute from sephorose-immobilized T.T. and anti-DR antisera, but not anti-lg antisera or the T40/25 monoclonal antibody, which binds a nonpolymorphic determinant on the human T cell receptor. These results demonstrate that human Ag specific helper factors exist, bind antigen and bear class II MHC determinants.

  6. Mutagenic effects of alpha particles in normal human skin fibroblasts

    SciTech Connect

    Chen, D.J.; Carpenter, S.; Hanks, T. [Los Alamos National Lab., NM (United States)

    1992-12-31

    Alpha-irradiation to the bronchial airways from inhaled radon progeny increases the risk of developing lung cancer. The molecular mechanism of radon-induced lung cancer is not clear, but one of the most important genetic effects of ionizing radiation is the induction of gene mutation. Mutations, especially those associated with visible chromosome abnormalities in humans, have been associated with cancer. Therefore, our objective is to use a well-defined model system to determine the mutagenic potential of alpha particles in normal human skin cells and to define this action at the molecular level. Normal human skin fibroblasts were irradiated with alpha particles (3.59 MeV, LET 115 keV {mu}m{sup {minus}1}) emitted from the decay of {sup 238}Pu. Mutagenicity was determined at the X-linked hypoxanthine guanine phosphoribosyl transferase (HPRT) locus. Results from this study indicate that beta particles were more efficient in mutation induction than gamma rays. Based on the initial slopes of the dose-response curves, the RBE for mutation is about 8 for alpha particles. HPRT-deficient mutants which are resistant to 6-thioguanine have been isolated and analyzed by the Southern blot technique. To date, we have characterized 69 gamma-ray-induced and 195 alpha-particle-induced HPRT-deficient mutants. Our data indicate that more than 50% of all gamma-ray-induced mutants have band patterns identical to that observed for the normal structural HPRT gene, whereas the remaining mutants (45%) contain either a rearrangement, partial deletion, or total deletion of the HPRT gene. In contrast, only 30% of alpha-particle-induced human HPRT mutants contain a normal Southern blot pattern, and about 50% indicate total deletion of the HPRT gene. Our results support the notion that high-LET radiation produces more unrepaired or misrepaired DNA damage than do gamma rays.

  7. Identification of a trpG-related glutamine amide transfer domain in Escherichia coli GMP synthetase.

    PubMed

    Zalkin, H; Argos, P; Narayana, S V; Tiedeman, A A; Smith, J M

    1985-03-25

    An improved method was developed to align related protein sequences and search for homology. A glutamine amide transfer domain was identified in an NH2-terminal segment of GMP synthetase from Escherichia coli. Amino acid residues 1-198 in GMP synthetase are homologous with the glutamine amide transfer domain in trpG X D-encoded anthranilate synthase component II-anthranilate phosphoribosyltransferase and the related pabA-encoded p-aminobenzoate synthase component II. This result supports a model for gene fusion in which a trpG-related glutamine amide transfer domain was recruited to augment the function of a primitive NH3-dependent GMP synthetase. Sequence analyses emphasize that glutamine amide transfer domains are thus far found only at the NH2 terminus of fused proteins. Two rules are formulated to explain trpG and trpG-related fusions. (i) trpG and trpG-related genes must have translocated immediately up-stream of genes destined for fusion in order to position a glutamine amide transfer domain at the NH2 terminus after fusion. (ii) trpG and trpG-related genes could not translocate adjacent to a regulatory region at the 5' end of an operon. These rules explain known trpG-like fusions and explain why trpG and pabA are not fused to trpE and pabB, respectively. Alignment searches of GMP synthetase with two other enzymes that bind GMP, E. coli amidophosphoribosyltransferase and human hypoxanthine-guanine phosphoribosyltransferase, suggest a structurally homologous segment which may constitute a GMP binding site. PMID:2982857

  8. Adipose Tissue–derived Mesenchymal Stem Cells Expressing Prodrug-converting Enzyme Inhibit Human Prostate Tumor Growth

    PubMed Central

    Cavarretta, Ilaria T; Altanerova, Veronika; Matuskova, Miroslava; Kucerova, Lucia; Culig, Zoran; Altaner, Cestmir

    2009-01-01

    The ability of human adipose tissue–derived mesenchymal stem cells (AT-MSCs), engineered to express the suicide gene cytosine deaminase::uracil phosphoribosyltransferase (CD::UPRT), to convert the relatively nontoxic 5-fluorocytosine (5-FC) into the highly toxic antitumor 5-fluorouracil (5-FU) together with their ability to track and engraft into tumors and micrometastases makes these cells an attractive tool to activate prodrugs directly within the tumor mass. In this study, we tested the feasibility and efficacy of these therapeutic cells to function as cellular vehicles of prodrug-activating enzymes in prostate cancer (PC) therapy. In in vitro migration experiments we have shown that therapeutic AT-MSCs migrated to all the prostate cell lines tested. In a pilot preclinical study, we observed that coinjections of human bone metastatic PC cells along with the transduced AT-MSCs into nude mice treated with 5-FC induced a complete tumor regression in a dose dependent manner or did not even allow the establishment of the tumor. More importantly, we also demonstrated that the therapeutic cells were effective in significantly inhibiting PC tumor growth after intravenous administration that is a key requisite for any clinical application of gene-directed enzyme prodrug therapies. PMID:19844197

  9. Efficient delivery of RNA interference oligonucleotides to polarized airway epithelia in vitro

    PubMed Central

    Ramachandran, Shyam; Krishnamurthy, Sateesh; Jacobi, Ashley M.; Wohlford-Lenane, Christine; Behlke, Mark A.; Davidson, Beverly L.

    2013-01-01

    Polarized and pseudostratified primary airway epithelia present barriers that significantly reduce their transfection efficiency and the efficacy of RNA interference oligonucleotides. This creates an impediment in studies of the airway epithelium, diminishing the utility of loss-of-function as a research tool. Here we outline methods to introduce RNAi oligonucleotides into primary human and porcine airway epithelia grown at an air-liquid interface and difficult-to-transfect transformed epithelial cell lines grown on plastic. At the time of plating, we reverse transfect small-interfering RNA (siRNA), Dicer-substrate siRNA, or microRNA oligonucleotides into cells by use of lipid or peptide transfection reagents. Using this approach we achieve significant knockdown in vitro of hypoxanthine-guanine phosphoribosyltransferase, IL-8, and CFTR expression at the mRNA and protein levels in 1–3 days. We also attain significant reduction of secreted IL-8 in polarized primary pig airway epithelia 3 days posttransfection and inhibition of CFTR-mediated Cl? conductance in polarized air-liquid interface cultures of human airway epithelia 2 wk posttransfection. These results highlight an efficient means to deliver RNA interference reagents to airway epithelial cells and achieve significant knockdown of target gene expression and function. The ability to reliably conduct loss-of-function assays in polarized primary airway epithelia offers benefits to research in studies of epithelial cell homeostasis, candidate gene function, gene-based therapeutics, microRNA biology, and targeting the replication of respiratory viruses. PMID:23624792

  10. Bacterial delivery of large intact genomic-DNA-containing BACs into mammalian cells

    PubMed Central

    Cheung, Wing; Kotzamanis, George; Abdulrazzak, Hassan; Goussard, Sylvie; Kaname, Tadashi; Kotsinas, Athanassios; Gorgoulis, Vassilis G.; Grillot-Courvalin, Catherine; Huxley, Clare

    2012-01-01

    Efficient delivery of large intact vectors into mammalian cells remains problematical. Here we evaluate delivery by bacterial invasion of two large BACs of more than 150 kb in size into various cells. First, we determined the effect of several drugs on bacterial delivery of a small plasmid into different cell lines. Most drugs tested resulted in a marginal increase of the overall efficiency of delivery in only some cell lines, except the lysosomotropic drug chloroquine, which was found to increase the efficiency of delivery by 6-fold in B16F10 cells. Bacterial invasion was found to be significantly advantageous compared with lipofection in delivering large intact BACs into mouse cells, resulting in 100% of clones containing intact DNA. Furthermore, evaluation of expression of the human hypoxanthine phosphoribosyltransferase (HPRT) gene from its genomic locus, which was present in one of the BACs, showed that single copy integrations of the HPRT-containing BAC had occurred in mouse B16F10 cells and that expression of HPRT from each human copy was 0.33 times as much as from each endogenous mouse copy. These data provide new evidence that bacterial delivery is a convenient and efficient method to transfer large intact therapeutic genes into mammalian cells. PMID:22095052

  11. Bacterial delivery of large intact genomic-DNA-containing BACs into mammalian cells.

    PubMed

    Cheung, Wing; Kotzamanis, George; Abdulrazzak, Hassan; Goussard, Sylvie; Kaname, Tadashi; Kotsinas, Athanassios; Gorgoulis, Vassilis G; Grillot-Courvalin, Catherine; Huxley, Clare

    2012-01-01

    Efficient delivery of large intact vectors into mammalian cells remains problematical. Here we evaluate delivery by bacterial invasion of two large BACs of more than 150 kb in size into various cells. First, we determined the effect of several drugs on bacterial delivery of a small plasmid into different cell lines. Most drugs tested resulted in a marginal increase of the overall efficiency of delivery in only some cell lines, except the lysosomotropic drug chloroquine, which was found to increase the efficiency of delivery by 6-fold in B16F10 cells. Bacterial invasion was found to be significantly advantageous compared with lipofection in delivering large intact BACs into mouse cells, resulting in 100% of clones containing intact DNA. Furthermore, evaluation of expression of the human hypoxanthine phosphoribosyltransferase (HPRT) gene from its genomic locus, which was present in one of the BACs, showed that single copy integrations of the HPRT-containing BAC had occurred in mouse B16F10 cells and that expression of HPRT from each human copy was 0.33 times as much as from each endogenous mouse copy. These data provide new evidence that bacterial delivery is a convenient and efficient method to transfer large intact therapeutic genes into mammalian cells. PMID:22095052

  12. Molecular epidemiology studies on occupational and environmental exposure to mutagens and carcinogens, 1997-1999.

    PubMed Central

    Srám, R J; Binková, B

    2000-01-01

    Molecular epidemiology is a new and evolving area of research, combining laboratory measurement of internal dose, biologically effective dose, biologic effects, and influence of individual susceptibility with epidemiologic methodologies. Biomarkers evaluated were selected according to basic scheme: biomarkers of exposure--metabolites in urine, DNA adducts, protein adducts, and Comet assay parameters; biomarkers of effect--chromosomal aberrations, sister chromatid exchanges, micronuclei, mutations in the hypoxanthine-guanine phosphoribosyltransferase gene, and the activation of oncogenes coding for p53 or p21 proteins as measured on protein levels; biomarkers of susceptibility--genetic polymorphisms of genes CYP1A1, GSTM1, GSTT1, NAT2. DNA adducts measured by 32P-postlabeling are the biomarker of choice for the evaluation of exposure to polycyclic aromatic hydrocarbons. Protein adducts are useful as a biomarker for exposure to tobacco smoke (4-aminobiphenyl) or to smaller molecules such as acrylonitrile or 1,3-butadiene. Of the biomarkers of effect, the most common are cytogenetic end points. Epidemiologic studies support the use of chromosomal breakage as a relevant biomarker of cancer risk. The use of the Comet assay and methods analyzing oxidative DNA damage needs reliable validation for human biomonitoring. Until now there have not been sufficient data to interpret the relationship between genotypes, biomarkers of exposure, and biomarkers of effect for assessing the risk of human exposure to mutagens and carcinogens. PMID:10698723

  13. Selection of suitable reference genes for expression analysis in human glioma using RT-qPCR.

    PubMed

    Grube, Susanne; Göttig, Tatjana; Freitag, Diana; Ewald, Christian; Kalff, Rolf; Walter, Jan

    2015-05-01

    In human glioma research, quantitative real-time reverse-transcription PCR is a frequently used tool. Considering the broad variation in the expression of candidate reference genes among tumor stages and normal brain, studies using quantitative RT-PCR require strict definition of adequate endogenous controls. This study aimed at testing a panel of nine reference genes [beta-2-microglobulin, cytochrome c-1 (CYC1), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), hydroxymethylbilane synthase, hypoxanthine guanine phosphoribosyl transferase 1, ribosomal protein L13a (RPL13A), succinate dehydrogenase, TATA-box binding protein and 14-3-3 protein zeta] to identify and validate the most suitable reference genes for expression studies in human glioma of different grades (World Health Organization grades II-IV). After analysis of the stability values calculated using geNorm, NormFinder, and BestKeeper algorithms, GAPDH, RPL13A, and CYC1 can be indicated as reference genes applicable for accurate normalization of gene expression in glioma compared with normal brain and anaplastic astrocytoma or glioblastoma alone within this experimental setting. Generally, there are no differences in expression levels and variability of candidate genes in glioma tissue compared to normal brain. But stability analyses revealed just a small number of genes suitable for normalization in each of the tumor subgroups and across these groups. Nevertheless, our data show the importance of validation of adequate reference genes prior to every study. PMID:25862007

  14. Crucial involvement of xanthine oxidase in the intracellular signalling networks associated with human myeloid cell function

    PubMed Central

    Abooali, Maryam; Lall, Gurprit S.; Coughlan, Karen; Lall, Harjinder S.; Gibbs, Bernhard F.; Sumbayev, Vadim V.

    2014-01-01

    Xanthine oxidase (XOD) is an enzyme which plays a central role in purine catabolism by converting hypoxanthine into xanthine and then further into uric acid. Here we report that XOD is activated in THP-1 human myeloid cells in response to pro-inflammatory and growth factor stimulation. This effect occurred following stimulation of THP-1 cells with ligands of plasma membrane associated TLRs 2 and 4, endosomal TLRs 7 and 8 as well as stem cell growth factor (SCF). Hypoxia-inducible factor 1 (HIF-1) and activator protein 1 (AP-1) transcription complexes were found to be responsible for XOD upregulation. Importantly, the mammalian target of rapamycin (mTOR), a major myeloid cell translation regulator, was also found to be essential for XOD activation. Specific inhibition of XOD by allopurinol and sodium tungstate led to an increase in intracellular AMP levels triggering downregulation of mTOR activation by phosphorylation of its T2446 residue. Taken together, our results demonstrate for the first time that XOD is not only activated by pro-inflammatory stimuli or SCF but also plays an important role in maintaining mTOR-dependent translational control during the biological responses of human myeloid cells. PMID:25200751

  15. Orotate Phosphoribosyltransferase from Corynebacterium ammoniagenes Lacking a Conserved Lysine

    Microsoft Academic Search

    Xing Wang; Cuiqing Ma; Xiuwen Wang; Ping Xu

    2007-01-01

    by Mn2 and Co2. The optimal pH for the forward (phosphoribosyl transfer) reaction is 10.5 to 11.5, which is higher than that of other reported OPRTases, and the optimal pH for the reverse (pyrophosphorolysis) reaction is 5.5 to 6.5. The Km values for the four substrates were determined to be 33 M for orotate, 64 M for 5-phosphoribosyl-1-pyrophosphate (PRPP), 45

  16. Development and application of human cell lines engineered to metabolically activate structurally diverse environmental mutagens

    NASA Astrophysics Data System (ADS)

    Crespi, C. I.; Langenbach, Robert; Gonzalez, Frank J.; Gelboin, Harry V.; Penman, B. W.

    1993-03-01

    Cytochromes P450 are responsible for the mutagenic/carcinogenic activation of many environmental promutagens/procarcinogens. These enzymes are present at highest concentrations in liver in vivo but are markedly absent in tester organisms for most in vitro mutagenicity test systems. Two approaches have been used to supply needed metabolic activation, incorporation of an extracellular activating system, usually derived from a rodent liver and introduction of activating enzymes into the target cell. The latter approach appears to result in a more sensitive testing system because of the close proximity of the activating enzymes and the target DNA. Human cell lines have been developed which stably express human cytochromes P450 and other cDNAs which have been introduced individually or in combination. The resulting cell lines are exquisitely sensitive to exposure to promutagens and procarcinogens. Mutagenicity is measured at the hypoxanthine phosphoribosyl transferase (hprt) and thymidine kinase (tk) gene loci. The most versatile cell line, designated MCL-5, stably express five cDNAs encoding all of the human hepatic P450s known to be principally responsible for known human procarcinogen activation. The induction of mutation is observed in MCL-5 cells upon exposure to ng/ml levels of model compounds such as nitrosamines, aflatoxin B1 and benzo(a)pyrene. A lower volume mutagenicity assay has been developed for use with samples available in limited amounts. Human lymphoblast mutation assays have been used to screen for mutagenic activity sediment samples from a polluted watershed. Two sediment samples were found to have mutagenic activity to human lymphoblasts.

  17. Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease

    PubMed Central

    Jones, Simon P.; Franco, Nunzio F.; Varney, Bianca; Sundaram, Gayathri; Brown, David A.; de Bie, Josien; Lim, Chai K.; Guillemin, Gilles J.; Brew, Bruce J.

    2015-01-01

    The kynurenine pathway is a fundamental mechanism of immunosuppression and peripheral tolerance. It is increasingly recognized as playing a major role in the pathogenesis of a wide variety of inflammatory, neurodegenerative and malignant disorders. However, the temporal dynamics of kynurenine pathway activation and metabolite production in human immune cells is currently unknown. Here we report the novel use of flow cytometry, combined with ultra high-performance liquid chromatography and gas chromatography-mass spectrometry, to sensitively quantify the intracellular expression of three key kynurenine pathway enzymes and the main kynurenine pathway metabolites in a time-course study. This is the first study to show that up-regulation of indoleamine 2,3-dioxygenase (IDO-1), kynurenine 3-monoxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) is lacking in lymphocytes treated with interferon gamma. In contrast, peripheral monocytes showed a significant elevation of kynurenine pathway enzymes and metabolites when treated with interferon gamma. Expression of IDO-1, KMO and QPRT correlated significantly with activation of the kynurenine pathway (kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin. Our results also describe an original and sensitive methodological approach to quantify kynurenine pathway enzyme expression in cells. This has revealed further insights into the potential role of these enzymes in disease processes. PMID:26114426

  18. Method for the production of human T-T cell hybrids and production suppressor factor by human T-T cell hybrids

    SciTech Connect

    Platsoucas, C.

    1989-06-27

    This patent describes a method for production of human T-T cell hybrids which produce Suppressor Factor wherein cells of lymphoid origin are fused with comprises: (a) mixing cells from a first parent cell line comprising a non-mutagenized Jurkat lymoblastoid T cell line, wherein the Jurkat lymphoblastoid cells are not sensitive and cannot be killed by hypoxanthine-aminopterin-thymidine medium, with a second parent cell comprising mitogen or alloantigen activated peripheral blood leukocyte T cells or purified T-cells, (b) allowing the first and second parent cells to fuse in the presence of polyethylene glycol for about 10-20 minutes with gentle agitation to generate hybrids in the cell mixture, (c) incubating the cell mixture containing the hybrids and the first and second parent cells, after removal of the polyethylene glycol, for periods of between one to sixty days at 37{sup 0} in 5% CO/sub 2/, (d) selecting for the hybrids by separating the hybrids from the first parent Jurkat lymphoblastoid cells by coloning in agar medium wherein the hybrids form colonies, (e) recovering the hybrids that form colonies in agar medium and expanding them in culture, and (f) determining the presence of Suppressor Factor in the culture and recovering the T-T cell hybrids which produce suppressor factor.

  19. Mutation induction in mammalian cells by accelerated heavy ions

    NASA Astrophysics Data System (ADS)

    Rosendahl, Ilja M.; Baumstark-Khan, Christa; Rink, Hermann

    The deleterious effects of accelerated heavy ions on living cells are of increasing importance for long duration human space flight activities. An important aspect of this field is attributed to the type and quality of biological damage induced by these densely ionizing particles. To address this aspect, cell inactivation and mutation induction at the HPRT locus (coding for hypoxanthine guanine phosphoribosyltransferase) was investigated in cultured V79 Chinese Hamster Cells irradiated with accelerated heavy ions (16-O, 40-Ca, 197-Au, and 238-U) and X-rays. Specific energies of the ions ranged from 1.9 to 69.7 MeV/u and corresponding LET values were between 62 and 15,580 keV ?m -1. While inactivation cross-sections ( ?i) rise over the whole LET range, mutation induction cross-sections ( ?m) increase up to approximately 300 keV ?m -1 (O-ions) but decline with heavier ions and more extreme LET values. A similar behavior is seen with mutation frequency dependent on particle fluence. After irradiation with accelerated uranium ions (8.8 MeV/u, 15,580 keV ?m -1) a significant decrease of mutation frequency was found with higher particle fluences (3 × 10 6 particles cm -2). Nearly no mutants were recovered with 8 × 10 6 particles cm -2.

  20. Influence of DNA Repair on Nonlinear Dose-Responses for Mutation

    PubMed Central

    Johnson, George E.

    2013-01-01

    Recent evidence has challenged the default assumption that all DNA-reactive alkylating agents exhibit a linear dose-response. Emerging evidence suggests that the model alkylating agents methyl- and ethylmethanesulfonate and methylnitrosourea (MNU) and ethylnitrosourea observe a nonlinear dose-response with a no observed genotoxic effect level (NOGEL). Follow-up mechanistic studies are essential to understand the mechanism of cellular tolerance and biological relevance of such NOGELs. MNU is one of the most mutagenic simple alkylators. Therefore, understanding the mechanism of mutation induction, following low-dose MNU treatment, sets precedence for weaker mutagenic alkylating agents. Here, we tested MNU at 10-fold lower concentrations than a previous study and report a NOGEL of 0.0075 µg/ml (72.8nM) in human lymphoblastoid cells, quantified through the hypoxanthine (guanine) phosphoribosyltransferase assay (OECD 476). Mechanistic studies reveal that the NOGEL is dependent upon repair of O6-methylguanine (O6MeG) by the suicide enzyme O6MeG-DNA methyltransferase (MGMT). Inactivation of MGMT sensitizes cells to MNU-induced mutagenesis and shifts the NOGEL to the left on the dose axis. PMID:23288051

  1. Cloning of rabbit HPRT gene using the recombineering system.

    PubMed

    Shi, Jianjun; Cai, Donghui; Chen, Xuejin; Sheng, Huizheng

    2007-08-01

    Hypoxanthine phosphoribosyltransferase (HPRT) plays an important role in the metabolic salvage of purines, and been used as an alternative pathway for mutant selection in many studies. To facilitate its application in rabbits, we have cloned the cDNA and genomic DNA of the rabbit HPRT gene using an approach that combines bioinformatics and recombineering methods. The cDNA is comprised of 1449 bp containing a coding sequence for a protein of 218 amino acids. The deduced amino acid sequence of the rabbit HPRT gene shares 98%, 97%, 98% and 94% identity with human, mouse, pig and cattle HPRT genes, respectively. Reverse transcription-polymerase chain reaction analysis showed that this gene is ubiquitously expressed in tissues of adult rabbit. The rabbit HPRT gene spans approximately 48 kb in length and consists of nine exons. The cloning of the rabbit HPRT gene shows the usefulness of the recombineering system in cloning genes of large size. This system may facilitate the subcloning of DNA from bacterial artificial chromosomes for cloning genes of large size or filling big gaps in genomic sequencing. PMID:17687494

  2. Expression of reference genes and T helper 17 associated cytokine genes in the equine intestinal tract.

    PubMed

    Hjertner, Bernt; Olofsson, Karin M; Lindberg, Ronny; Fuxler, Lisbeth; Fossum, Caroline

    2013-09-01

    There is accumulating evidence for the involvement of pro-inflammatory cytokines associated with a T helper 17 response in intestinal disorders such as inflammatory bowel disease (IBD) in humans. The involvement of interleukin (IL)-17 or IL-23 in equine IBD has not been studied and most gene expression studies in the equine intestine have been limited to the use of a single non-validated reference gene. In this study, expression of the reference gene candidates ?2 microglobulin (?2M), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), histone H2A type 1, hypoxanthine-guanine phosphoribosyltransferase (HPRT), 60S ribosomal protein L32 (RPL32), succinate dehydrogenase complex subunit A (SDHA) and transferrin receptor 1 protein coding (TFRC)in the equine intestine was evaluated by quantitative PCR. Three to four reference genes were adequate for normalisation of gene expression in the healthy duodenum, mid-jejunum, colon and rectum, although each segment required a unique combination of reference genes. No combination of the evaluated genes was optimal for the caecum and ileum. Another combination of reference genes (GAPDH, HPRT, RPL32 and SDHA) was optimal for normalisation of rectal samples from healthy and IBD-affected horses, indicating that reference genes should be re-evaluated if material from diseased specimens is analysed. Basal expression of IL-12p40, IL-17A and IL-23p19 was detected in each segment, which will enable gene expression studies of these cytokines by relative quantification. PMID:23810185

  3. Escape from Het-6 Incompatibility in Neurospora Crassa Partial Diploids Involves Preferential Deletion within the Ectopic Segment

    PubMed Central

    Smith, M. L.; Yang, C. J.; Metzenberg, R. L.; Glass, N. L.

    1996-01-01

    Self-incompatible het-6(OR)/het-6(PA) partial diploids of Neurospora crassa were selected from a cross involving the translocation strain, T(IIL -> IIIR)AR18, and a normal sequence strain. About 25% of the partial diploids exhibited a marked increase in growth rate after 2 weeks, indicating that ``escape'' from het-6 incompatibility had occurred. Near isogenic tester strains with different alleles (het-6(OR) and het-6(PA)) were constructed and used to determine that 80 of 96 escape strains tested were het-6(PA), retaining the het-6 allele found in the normal-sequence LGII position; 16 were het-6(OR), retaining the allele in the translocated position. Restriction fragment length polymorphisms in 45 escape strains were examined with probes made from cosmids that spanned the translocated region. Along with electrophoretic analysis of chromosomes from three escape strains, RFLPs showed that escape is associated with deletion of part of one or the other of the duplicated DNA segments. Deletions ranged in size from ~70 kbp up to putatively the entire 270-kbp translocated region but always included a 35-kbp region wherein we hypothesize het-6 is located. The deletion spectrum at het-6 thus resembles other cases where mitotic deletions occur such as of tumor suppressor genes and of the hprt gene (coding for hypoxanthine-guanine phosphoribosyl-transferase) in humans. PMID:8889517

  4. In vitro susceptibilities of Plasmodium falciparum to compounds which inhibit nucleotide metabolism.

    PubMed Central

    Queen, S A; Jagt, D L; Reyes, P

    1990-01-01

    A unique metabolic feature of malaria parasites is their restricted ability to synthesize nucleotides. These parasites are unable to synthesize the purine ring and must therefore obtain preformed purine bases and nucleosides from the host cell, the erythrocyte. On the other hand, pyrimidines must be synthesized de novo because of the inability of the parasites to salvage preformed pyrimidines. Thus, one would anticipate that the blockage of purine salvage or pyrimidine de novo synthesis should adversely affect parasite growth. This premise was tested in vitro with a total of 64 compounds, mostly purine and pyrimidine analogs, known to inhibit one or more steps of nucleotide synthesis. Of the 64 compounds, 22 produced a 50% inhibition of the growth of the human malaria parasite Plasmodium falciparum at a concentration of 50 microM or less. Inhibition of the growth of chloroquine-resistant clones of P. falciparum did not differ significantly from that of the growth of chloroquine-susceptible clones. Two of the compounds which effectively inhibited parasite growth, 6-mercaptopurine and 6-thioguanine, were found to be potent competitive inhibitors of a key purine-salvaging enzyme (hypoxanthine-guanine-xanthine phosphoribosyltransferase) of the parasite. PMID:2201255

  5. Capillary bioreactors based on human purine nucleoside phosphorylase: a new approach for ligands identification and characterization.

    PubMed

    de Moraes, Marcela Cristina; Ducati, Rodrigo Gay; Donato, Augusto José; Basso, Luiz Augusto; Santos, Diógenes Santiago; Cardoso, Carmen Lucia; Cass, Quezia Bezerra

    2012-04-01

    The enzyme purine nucleoside phosphorylase (PNP) is a target for the discovery of new lead compounds employed on the treatment severe T-cell mediated disorders. Within this context, the development of new, direct, and reliable methods for ligands screening is an important task. This paper describes the preparation of fused silica capillaries human PNP (HsPNP) immobilized enzyme reactor (IMER). The activity of the obtained IMER is monitored on line in a multidimensional liquid chromatography system, by the quantification of the product formed throughout the enzymatic reaction. The K(M) value for the immobilized enzyme was about twofold higher than that measured for the enzyme in solution (255 ± 29.2 ?M and 133 ± 14.9 ?M, respectively). A new fourth-generation immucillin derivative (DI4G; IC(50)=40.6 ± 0.36 nM), previously identified and characterized in HsPNP free enzyme assays, was used to validate the IMER as a screening method for HsPNP ligands. The validated method was also used for mechanistic studies with this inhibitor. This new approach is a valuable tool to PNP ligand screening, since it directly measures the hypoxanthine released by inosine phosphorolysis, thus furnishing more reliable results than those one used in a coupled enzymatic spectrophotometric assay. PMID:22099222

  6. A system for assaying homologous recombination at the endogenous human thymidine kinase gene.

    PubMed Central

    Benjamin, M B; Potter, H; Yandell, D W; Little, J B

    1991-01-01

    A system for assaying human interchromosomal recombination in vitro was developed, using a cell line containing two different mutant thymidine kinase genes (TK) on chromosomes 17. Heteroalleles were generated in the TK+/+ parent B-lymphoblast cell line WIL-2 by repeated exposure to the alkylating nitrogen mustard ICR-191, which preferentially causes +1 or -1 frameshifts. Resulting TK-/- mutants were selected in medium containing the toxic thymidine analog trifluorothymidine. Mutations were characterized by exon-specific polymerase chain reaction amplification and direct sequencing. In two lines, heterozygous frameshifts were located in exons 4 and 7 of the TK gene separated by approximately 8 kilobases. These lines undergo spontaneous reversion to TK+ at a frequency of less than 10(-7), and revertants can be selected in cytidine/hypoxanthine/aminopterin/thymidine medium. The nature and location of these heteroallelic mutations make large deletions, rearrangements, nondisjunction, and reduplication unlikely mechanisms for reversion to TK+. The mode of reversion to TK+ was specifically assessed by DNA sequencing, use of single-strand conformation polymorphisms, and analysis of various restriction fragment length polymorphisms (RFLPs) linked to the TK gene on chromosome 17. Our data suggest that a proportion of revertants has undergone recombination and gene conversion at the TK locus, with concomitant loss of frameshifts and allele loss at linked RFLPs. Models are presented for the origin of two recombinants. Images PMID:1677771

  7. ‘Human, Still Human

    Microsoft Academic Search

    Jérôme Bindé

    2005-01-01

    For more than a century the shifts in western thought have witnessed: the death of God, the demise of political ideologies that appeared to have taken over from ‘divine’ values, and the solitude of the disoriented individual. The individual’s malaise may be the symptom of a questioning of the very notion of being human. Adopting the critique of humanism introduced

  8. Oral glycotoxins are a modifiable cause of dementia and the metabolic syndrome in mice and humans

    PubMed Central

    Cai, Weijing; Uribarri, Jaime; Zhu, Li; Chen, Xue; Swamy, Shobha; Zhao, Zhengshan; Grosjean, Fabrizio; Simonaro, Calogera; Kuchel, George A.; Schnaider-Beeri, Michal; Woodward, Mark; Striker, Gary E.; Vlassara, Helen

    2014-01-01

    Age-associated dementia and Alzheimer’s disease (AD) are currently epidemic. Neither their cause nor connection to the metabolic syndrome (MS) is clear. Suppression of deacetylase survival factor sirtuin 1 (SIRT1), a key host defense, is a central feature of AD. Age-related MS and diabetes are also causally associated with suppressed SIRT1 partly due to oxidant glycotoxins [advanced glycation end products (AGEs)]. Changes in the modern diet include excessive nutrient-bound AGEs, such as neurotoxic methyl-glyoxal derivatives (MG). To determine whether dietary AGEs promote AD, we evaluated WT mice pair-fed three diets throughout life: low-AGE (MG?), MG-supplemented low-AGE (MG+), and regular (Reg) chow. Older MG+-fed mice, similar to old Reg controls, developed MS, increased brain amyloid-?42, deposits of AGEs, gliosis, and cognitive deficits, accompanied by suppressed SIRT1, nicotinamide phosphoribosyltransferase, AGE receptor 1, and PPAR?. These changes were not due to aging or caloric intake, as neither these changes nor the MS were present in age-matched, pair-fed MG? mice. The mouse data were enhanced by significant temporal correlations between high circulating AGEs and impaired cognition, as well as insulin sensitivity in older humans, in whom dietary and serum MG levels strongly and inversely associated with SIRT1 gene expression. The data identify a specific AGE (MG) as a modifiable risk factor for AD and MS, possibly acting via suppressed SIRT1 and other host defenses, to promote chronic oxidant stress and inflammation. Because SIRT1 deficiency in humans is both preventable and reversible by AGE reduction, a therapeutic strategy that includes AGE reduction may offer a new strategy to combat the epidemics of AD and MS. PMID:24567379

  9. Human bites

    MedlinePLUS

    Bites - human ... Human bites that break the skin, like all puncture wounds, have a high risk of infection. They ... bite to express anger or other negative feelings. Human bites may be more dangerous than most animal ...

  10. Attenuated variants of Lesch-Nyhan disease

    PubMed Central

    Ceballos-Picot, Irene; Torres, Rosa J.; Visser, Jasper E.; Schretlen, David J.; Verdu, Alfonso; Laróvere, Laura E.; Chen, Chung-Jen; Cossu, Antonello; Wu, Chien-Hui; Sampat, Radhika; Chang, Shun-Jen; de Kremer, Raquel Dodelson; Nyhan, William; Harris, James C.; Reich, Stephen G.; Puig, Juan G.

    2010-01-01

    Lesch–Nyhan disease is a neurogenetic disorder caused by deficiency of the enzyme hypoxanthine–guanine phosphoribosyltransferase. The classic form of the disease is described by a characteristic syndrome that includes overproduction of uric acid, severe generalized dystonia, cognitive disability and self-injurious behaviour. In addition to the classic disease, variant forms of the disease occur wherein some clinical features are absent or unusually mild. The current studies provide the results of a prospective and multi-centre international study focusing on neurological manifestations of the largest cohort of Lesch–Nyhan disease variants evaluated to date, with 46 patients from 3 to 65 years of age coming from 34 families. All had evidence for overproduction of uric acid. Motor abnormalities were evident in 42 (91%), ranging from subtle clumsiness to severely disabling generalized dystonia. Cognitive function was affected in 31 (67%) but it was never severe. Though none exhibited self-injurious behaviours, many exhibited behaviours that were maladaptive. Only three patients had no evidence of neurological dysfunction. Our results were compared with a comprehensive review of 78 prior reports describing a total of 127 Lesch–Nyhan disease variants. Together these results define the spectrum of clinical features associated with hypoxanthine–guanine phosphoribosyltransferase deficiency. At one end of the spectrum are patients with classic Lesch–Nyhan disease and the full clinical phenotype. At the other end of the spectrum are patients with overproduction of uric acid but no apparent neurological or behavioural deficits. Inbetween are patients with varying degrees of motor, cognitive, or behavioural abnormalities. Recognition of this spectrum is valuable for understanding the pathogenesis and diagnosis of all forms of hypoxanthine–guanine phosphoribosyltransferase deficiency. PMID:20176575

  11. Human rights

    Microsoft Academic Search

    B. de Gaay Fortman

    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 and generally accessible mechanisms for implementation. That mission got a major impetus with

  12. 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

    NASA Technical Reports Server (NTRS)

    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.

  13. Lesch-Nyhan Syndrome in a Family with a Deletion Followed by an Insertion within the HPRT1 Gene.

    PubMed

    Nguyen, Khue Vu; Nyhan, William L

    2015-06-01

    Lesch-Nyhan syndrome (LNS) is a rare X-linked inherited neurogenetic disorder of purine metabolism in which the enzyme, hypoxanthine-guanine phosphoribosyltransferase(HGprt) is defective. The authors report a novel mutation which led to LNS in a family with a deletion followed by an insertion (INDELS) via the serial replication slippage mechanism: c.428_432delTGCAGinsAGCAAA, p.Met143Lysfs*12 in exon 6 of HPRT1 gene. Molecular diagnosis discloses the genetic heterogeneity of HPRT1 gene responsible for HGprt deficiency. It allows fast, accurate carrier detection and genetic counseling. PMID:25965333

  14. Glial cells metabolically cooperate: a potential requirement for gene replacement therapy.

    PubMed Central

    Gruber, H E; Koenker, R; Luchtman, L A; Willis, R C; Seegmiller, J E

    1985-01-01

    Immunofluorescently labeled glial cells are shown by radioautography to metabolically cooperate with hypoxanthine phosphoribosyltransferase-deficient fibroblasts. The observations of cooperation without cell contact and of incorporation gradients around the glial cells suggest that cooperation occurs through extracellular transport of radiolabeled purine compounds. The transfer of radiolabeled adenine, adenosine, or methylthioadeninosine is supported by the quantitative loss of cooperation when the recipient cell is also deficient in enzymes required for adenine or adenosine salvage. The demonstration of glial cell cooperation provides impetus for current research toward gene replacement therapy for the neurologic symptoms of the Lesch-Nyhan syndrome. Images PMID:2995977

  15. The Human Spark: Being Human

    NSDL National Science Digital Library

    2012-06-12

    This lesson plan from PBS covers a variety of biology topics related to the human as an animal. Students will view and discuss segments from the PBS program The Human Spark. In the first learning activity, the class will explore how human thought differs from that of other species. In the second learning activity, students will examine different traits and abilities, how these abilities have evolved to help humans deal with their environment, and how they distinguish humans from other animals.

  16. Human Anatomy

    NSDL National Science Digital Library

    Ms. Schultz

    2007-11-09

    Please find links below: Human Anatomy Human Anatomy Online Human Body - Gray s Anatomy - Digestive Aparatus MEDtropolis - Virtual Body - can be viewed in English or Spanish. Contains tours of the Human Brain, Skeleton, Human Heart, and Digestive Tract. Respiratory System National Heart, Lung, and Blood Institute HealthTalk COPD (chronic obstructive pulmonary disease) American Lung Association - Disease Finder Association of Legal Aid Attorneys/UAW 2325 Canadian Lung Association Kids Health Family Living and Personal Living - Ms. Schultz added this link because on this page there is CDC, American ...

  17. Charged-particle mutagenesis II. Mutagenic effects of high energy charged particles in normal human fibroblasts

    NASA Astrophysics Data System (ADS)

    Chen, D. J.; Tsuboi, K.; Nguyen, T.; Yang, T. C.

    1994-10-01

    The biological effects of high LET charged particles are a subject of great concern with regard to the prediction of radiation risk in space. In this report, mutagenic effects of high LET charged particles are quantitatively measured using primary cultures of human skin fibroblasts, and the spectrum of induced mutations are analyzed. The LET of the charged particles ranged from 25 KeV/?m to 975 KeV/gmm with particle energy (on the cells) between 94 - 603 MeV/u. The X-chromosome linked hypoxanthine guanine phosphoribosyl transferase (hprt) locus was used as the target gene. Exposure to these high LET charged particles resulted in exponential survival curves; whereas, mutation induction was fitted by a linear model. The Relative Biological Effect (RBE) for cell-killing ranged from 3.73 to 1.25, while that for mutant induction ranged from 5.74 to 0.48. Maximum RBE values were obtained at the LET of 150 keV/?m. The inactivation cross-section (?i) and the action-section for mutant induction (?m) ranged from 2.2 to 92.0 ?m2 and 0.09 to 5.56 × 10-3 ?m2, respectively. The maximum values were obtained by 56Fe with an LET of 200 keV/?m. The mutagenicity (?m/?i) ranged from 2.05 to 7.99 × 10-5 with the maximum value at 150 keV/?m. Furthermore, molecular analysis of mutants induced by charged particles indicates that higher LET beams are more likely to cause larger deletions in the hprt locus.

  18. Charged-particle mutagenesis 2. Mutagenic effects of high energy charged particles in normal human fibroblasts

    NASA Technical Reports Server (NTRS)

    Chen, D. J.; Tsuboi, K.; Nguyen, T.; Yang, T. C.

    1994-01-01

    The biological effects of high Linear Energy Transfer (LET) charged particles are a subject of great concern with regard to the prediction of radiation risk in space. In this report, mutagenic effects of high LET charged particles are quantitatively measured using primary cultures of human skin fibroblasts, and the spectrum of induced mutations are analyzed. The LET of the charged particles ranged from 25 KeV/micrometer to 975 KeV/micrometer with particle energy (on the cells) between 94-603 MeV/u. The X-chromosome linked hypoxanthine guanine phosphoribosyl transferase (hprt) locus was used as the target gene. Exposure to these high LET charged particles resulted in exponential survival curves; whereas, mutation induction was fitted by a linear model. The Relative Biological Effect (RBE) for cell-killing ranged from 3.73 to 1.25, while that for mutant induction ranged from 5.74 to 0.48. Maximum RBE values were obtained at the LET of 150 keV/micrometer. The inactivation cross-section (alpha i) and the action cross-section for mutant induction (alpha m) ranged from 2.2 to 92.0 sq micrometer and 0.09 to 5.56 x 10(exp -3) sq micrometer respectively. The maximum values were obtained by Fe-56 with an LET of 200 keV/micrometer. The mutagenicity (alpha m/alpha i) ranged from 2.05 to 7.99 x 10(exp -5) with the maximum value at 150 keV/micrometer. Furthermore, molecular analysis of mutants induced by charged particles indicates that higher LET beams are more likely to cause larger deletions in the hprt locus.

  19. Charged-particle mutagenesis II. Mutagenic effects of high energy charged particles in normal human fibroblasts

    NASA Technical Reports Server (NTRS)

    Chen, D. J.; Tsuboi, K.; Nguyen, T.; Yang, T. C.

    1994-01-01

    The biological effects of high LET charged particles are a subject of great concern with regard to the prediction of radiation risk in space. In this report, mutagenic effects of high LET charged particles are quantitatively measured using primary cultures of human skin fibroblasts, and the spectrum of induced mutations are analyzed. The LET of the charged particles ranged from 25 KeV/micrometer to 975 KeV/micrometer with particle energy (on the cells) between 94-603 MeV/u. The X-chromosome linked hypoxanthine guanine phosphoribosyl transferase (hprt) locus was used as the target gene. Exposure to these high LET charged particles resulted in exponential survival curves; whereas, mutation induction was fitted by a linear model. The Relative Biological Effect (RBE) for cell-killing ranged from 3.73 to 1.25, while that for mutant induction ranged from 5.74 to 0.48. Maximum RBE values were obtained at the LET of 150 keV/micrometer. The inactivation cross-section (alpha i) and the action cross-section for mutant induction (alpha m) ranged from 2.2 to 92.0 micrometer2 and 0.09 to 5.56 x 10(-3) micrometer2, respectively. The maximum values were obtained by 56Fe with an LET of 200 keV/micrometer. The mutagenicity (alpha m/alpha i) ranged from 2.05 to 7.99 x 10(-5) with the maximum value at 150 keV/micrometer. Furthermore, molecular analysis of mutants induced by charged particles indicates that higher LET beams are more likely to cause larger deletions in the hprt locus.

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

    NASA Technical Reports Server (NTRS)

    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.

  1. Human Papillomavirus and Human Disease

    Microsoft Academic Search

    1997-01-01

    Human papillomaviruses (HPVs) are associated with a spectrum of different diseases in humans, including common warts and genital warts. Of more serious concern is the connection between certain HPV types and some malignancies, particularly cervical and anal cancer. DNA from HPV-16 and HPV-18, two types frequently found in cervical cancer tissue, can immortalize cells in laboratory cultures, unlike DNA from

  2. Human Evolution

    NSDL National Science Digital Library

    Lee, Amy.

    2002-01-01

    The first Web site is an article from the New York Times (1) detailing some recent fossil discoveries that are shaking the paleontological world (free registration is required). Another relatively recent article from Guardian Unlimited (2) discusses a scientific debate surrounding the question of whether "a Western lifestyle now protects humanity from the forces that used to shape Homo sapiens." The third resource (3) includes a likely timeline of events in the history of hominids and a tour of the fossil record. A second timeline from the Huntarian Museum and Art Gallery at the University of Glasgow (4) is less detailed, but links to many major fossil discoveries of human and pre-human history. An "overview of the study of human evolution, and of the currently accepted fossil evidence" (5) is used to inform arguments for creationists and evolutionists. An interesting site from the University of California Santa Barbara (6) (last mentioned in the December 1, 1998 Scout Report for Social Sciences) presents 3-dimensional views of "modern primate relatives and fossil ancestors of humans." The interactive documentary from the Institute of Human Origins (7) (last mentioned in the April 20, 2001 Scout Report) is a great resource for those with the Flash plug-in and a high speed connection. Lastly, a resource from PBS.org (8) focuses on human evolution in a format aimed at kids.

  3. Metabolism and selective toxicity of 6-nitrobenzylthioinosine in Toxoplasma gondii.

    PubMed

    el Kouni, M H; Guarcello, V; Al Safarjalani, O N; Naguib, F N

    1999-10-01

    The purine nucleoside analogue NBMPR (nitrobenzylthioinosine or 6-[(4-nitrobenzyl)thio]-9-beta-D-ribofuranosylpurine) was selectively phosphorylated to its nucleoside 5'-monophosphate by Toxoplasma gondii but not mammalian adenosine kinase (EC 2.7.1.20). NBMPR was also cleaved in toxoplasma to its nucleobase, nitrobenzylmercaptopurine. However, nitrobenzylmercaptopurine was not a substrate for either adenosine kinase or hypoxanthine-guanine-xanthine phosphoribosyltransferase (EC 2.4.2.8). Because of this unique and previously unknown metabolism of NBMPR by the parasite, the effect of NBMPR as an antitoxoplasmic agent was tested. NBMPR killed T. gondii grown in human fibroblasts in a dose-dependent manner, with a 50% inhibitory concentration of approximately 10 microM and without apparent toxicity to host cells. Doses of up to 100 microM had no significant toxic effect on uninfected host cells. The promising antitoxoplasmic effect of NBMPR led to the testing of other 6-substituted 9-beta-D-ribofuranosylpurines, which were shown to be good ligands of the parasite adenosine kinase (M. H. Iltzsch, S. S. Uber, K. O. Tankersley, and M. H. el Kouni, Biochem. Pharmacol. 49:1501-1512, 1995), as antitoxoplasmic agents. Among the analogues tested, 6-benzylthioinosine, p-nitrobenzyl-6-selenopurine riboside, N(6)-(p-azidobenzyl)adenosine, and N(6)-(p-nitrobenzyl)adenosine, like NBMPR, were selectively toxic to parasite-infected cells. Thus, it appears that the unique characteristics of purine metabolism in T. gondii render certain 6-substituted 9-beta-D-ribofuranosylpurines promising antitoxoplasmic drugs. PMID:10508021

  4. Carboxylated Short Single-Walled Carbon Nanotubes But Not Plain and Multi-walled Short Carbon Nanotubes Show in vitro Genotoxicity

    PubMed Central

    Mrakovcic, Maria; Meindl, Claudia; Leitinger, Gerd; Roblegg, Eva; Fröhlich, Eleonore

    2015-01-01

    Long carbon nanotubes (CNTs) resemble asbestos fibers due to their high length to diameter ratio and they thus have genotoxic effects. Another parameter that might explain their genotoxic effects is contamination with heavy metal ions. On the other hand, short (1–2 ?m) CNTs do not resemble asbestos fibers, and, once purified from contaminations, they might be suitable for medical applications. To identify the role of fiber thickness and surface properties on genotoxicity, well-characterized short pristine and carboxylated single-walled (SCNTs) and multi-walled (MCNTs) CNTs of different diameters were studied for cytotoxicity, the cell’s response to oxidative stress (immunoreactivity against hemoxygenase 1 and glutathione levels), and in a hypoxanthine guanine phosphoribosyltransferase (HPRT) assay using V79 chinese hamster fibroblasts and human lung adenocarcinoma A549 cells. DNA repair was demonstrated by measuring immunoreactivity against activated histone H2AX protein. The number of micronuclei as well as the number of multinucleated cells was determined. CNTs acted more cytotoxic in V79 than in A549 cells. Plain and carboxylated thin (<8 nm) SCNTs and MCNTs showed greater cytotoxic potential and carboxylated CNTs showed indication for generating oxidative stress. Multi-walled CNTs did not cause HPRT mutation, micronucleus formation, DNA damage, interference with cell division, and oxidative stress. Carboxylated, but not plain, SCNTs showed indication for in vitro DNA damage according to increase of H2AX-immunoreactive cells and HPRT mutation. Although short CNTs presented a low in vitro genotoxicity, functionalization of short SCNTs can render these particles genotoxic. PMID:25505129

  5. CONSEQUENCES OF IMPAIRED PURINE RECYCLING IN DOPAMINERGIC NEURONS

    PubMed Central

    Lewers, J. C.; Ceballos-Picot, I.; Shirley, T. L.; Mockel, L.; Egami, K.; Jinnah, H. A.

    2012-01-01

    A unique sensitivity to specific biochemical processes is responsible for selective vulnerability of midbrain dopamine neurons in several diseases. Prior studies have shown these neurons are susceptible to energy failure and mitochondrial dysfunction, oxidative stress, and impaired disposal of misfolded proteins. These neurons also are especially vulnerable to the loss of purine recycling. In the brains of humans or mice with inherited defects of the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT), the most prominent defect is loss of basal ganglia dopamine. To investigate the nature of the relationship between HPRT deficiency and dopamine, the mouse MN9D dopaminergic neuronal cell line was used to prepare 10 sublines lacking HPRT. The mutant sublines grew more slowly than the parent line, but without morphological signs of impaired viability. As a group, the mutant sublines had significantly lower dopamine than the parent line. The loss of dopamine in the mutants did not reflect impaired energy status, as judged by ATP levels or vulnerability to inhibitors of energy production. Indeed, the mutant lines as a group appeared energetically more robust than the parent line. The loss of dopamine also was not accompanied by enhanced susceptibility to oxidative stress or proteasome inhibitors. Instead, the loss of dopamine reflected only one aspect of a broad change in the molecular phenotype of the cells affecting mRNAs encoding tyrosine hydroxylase, the dopamine transporter, the vesicular monoamine transporter, monoamine oxidase B, catechol-O-methyltransferase, and GTP-cyclohydrolase. These changes were selective for the dopamine phenotype, since multiple control mRNAs were normal. These studies suggest purine recycling is an intrinsic metabolic process of particular importance to the molecular phenotype of dopaminergic neurons independent of previously established mechanisms involving energy failure, oxidative stress, or proteasome dysfunction. PMID:18313225

  6. Increased glyceraldehyde-3-phosphate dehydrogenase expression indicates higher survival rates in male patients with hepatitis B virus-accociated hepatocellular carcinoma and cirrhosis

    PubMed Central

    LIU, SHUANG; ZHU, PENGFEI; ZHANG, LING; LI, ZHUO; LV, QUANJUN; ZHENG, SUJUN; WANG, YANG; LU, FENGMIN

    2015-01-01

    Elevated expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been reported in different human malignancies. To understand its role in hepatitis B virus (HBV) infection-associated hepatocellular carcinoma (HCC), the expression of GAPDH was quantitatively measured in a cohort of 72 male HCC patients without preoperative treatment, all with evidence of chronic HBV infection. Using C-terminal banding protein 1 (CTBP1) or hypoxanthine phosphori-bosyltransferase 1 (HPRT1) as reference genes, the level of GAPDH mRNA in tumor tissue was found to be significantly higher compared with that in paired non tumor tissues (P=0.0087 for CTBP1; P=0.0116 for HPRT1). Accordingly, compared with the non-tumor tissue, 37.5% (27/72) of patients' tumor tissues had a more than 2-fold increase of GAPDH expression. Furthermore, following knockdown GAPDH expression via siRNA transient transfection, HepG2 cells exhibited enhanced resistance to cytosine arabinoside (IC50, 308.28 µM vs. 67.68 µM in the control; P=0.01). Notably, higher GAPDH expression was significantly associated with lower liver fibrosis score (P=0.0394) and a tendency towards higher survival rates for patients with HCC. To the best of our knowledge, the present study is the first study to report that the elevated expression levels of GAPDH in HCC tumor tissue may be relevant to an improved fibrosis score and survival probability in male patients with HBV infection; however, the underlying mechanism requires further investigation.

  7. A study of allelic polymorphism of four short tandem repeats in the population of northwestern Russia

    SciTech Connect

    Aseev, M.V.; Skakun, V.N.; Baranov, V.S. [Ott Institute of Obstetrics and Gynecology, St. Petersburg (Russian Federation)

    1995-06-01

    Characteristics of the allelic polymorphisms of the trimeric AGC repeat of the androgen receptor gene (Xq11-12), exon 1 (AR); the tetrameric ATCT repeat of the von Willebrand factor gene (12p12), intron 40 (vWF); the AGAT repeat of the hypoxanthine phosphoribosyltransferase gene (Xq26) (HPRT); and the AGAT repeat of anonymous DNA sequences of the short arm of chromosome X (STRX1) were studied in 160 DNA samples from unrelated inhabitants of northwestern Russia using the method of polymerase chain reaction. Seventeen, ten, eight, and nine alleles were revealed electrophoretically for short tandem repeats of AR, vWF, HPRT, and STRX1, respectively. The heterozygosity indices for these repeats were 0.80, 0.70, 0.54, and 0.58, respectively. The values for AR and vWF correlated with those expected according to the Hardy-Weinberg equilibrium, whereas the values for HPRT and STRX1 differed significantly from those theoretically expected. The individualization potentials were 0.045, 0.135, 0.095, and 0.061 for the short tandem repeats of AR, vWF, HPRT, and STRX1, respectively. The distribution of genotypes for the set of these four loci in the population studied was determined. The possibilities of using the studied polymorphic marker systems in molecular diagnosis of the corresponding monogenic diseases - spinal and bulbar muscle atrophy (AR), Lesch-Nyhan disease (HPRT), and von Willebrand disease (vWF) - as well as in population human genetics, testing of personal identity, and molecular approaches to the estimation of mutagenic activity are discussed. 17 refs., 2 figs., 6 tabs.

  8. Genetic Manipulation in ?ku80 Strains for Functional Genomic Analysis of Toxoplasma gondii

    PubMed Central

    Rommereim, Leah M.; Hortua Triana, Miryam A.; Falla, Alejandra; Sanders, Kiah L.; Guevara, Rebekah B.; Bzik, David J.; Fox, Barbara A.

    2013-01-01

    Targeted genetic manipulation using homologous recombination is the method of choice for functional genomic analysis to obtain a detailed view of gene function and phenotype(s). The development of mutant strains with targeted gene deletions, targeted mutations, complemented gene function, and/or tagged genes provides powerful strategies to address gene function, particularly if these genetic manipulations can be efficiently targeted to the gene locus of interest using integration mediated by double cross over homologous recombination. Due to very high rates of nonhomologous recombination, functional genomic analysis of Toxoplasma gondii has been previously limited by the absence of efficient methods for targeting gene deletions and gene replacements to specific genetic loci. Recently, we abolished the major pathway of nonhomologous recombination in type I and type II strains of T. gondii by deleting the gene encoding the KU80 protein1,2. The ?ku80 strains behave normally during tachyzoite (acute) and bradyzoite (chronic) stages in vitro and in vivo and exhibit essentially a 100% frequency of homologous recombination. The ?ku80 strains make functional genomic studies feasible on the single gene as well as on the genome scale1-4. Here, we report methods for using type I and type II ?ku80?hxgprt strains to advance gene targeting approaches in T. gondii. We outline efficient methods for generating gene deletions, gene replacements, and tagged genes by targeted insertion or deletion of the hypoxanthine-xanthine-guanine phosphoribosyltransferase (HXGPRT) selectable marker. The described gene targeting protocol can be used in a variety of ways in ?ku80 strains to advance functional analysis of the parasite genome and to develop single strains that carry multiple targeted genetic manipulations. The application of this genetic method and subsequent phenotypic assays will reveal fundamental and unique aspects of the biology of T. gondii and related significant human pathogens that cause malaria (Plasmodium sp.) and cryptosporidiosis (Cryptosporidium). PMID:23892917

  9. Bis(benzyl)polyamine analogs inhibit the growth of chloroquine-resistant human malaria parasites (Plasmodium falciparum) in vitro and in combination with alpha-difluoromethylornithine cure murine malaria.

    PubMed Central

    Bitonti, A J; Dumont, J A; Bush, T L; Edwards, M L; Stemerick, D M; McCann, P P; Sjoerdsma, A

    1989-01-01

    A number of bis(benzyl)polyamine analogs were found to be potent inhibitors of both chloroquine-resistant and chloroquine-sensitive strains of the human malaria parasite Plasmodium falciparum in vitro (IC50 values = 0.2-14 microM). Administration of one of the compounds, MDL 27695, which is N,N'-bis(3-[(phenylmethyl)amino]propyl)-1,7-diaminoheptane (C6H5CH2NH(CH2)3NH(CH2)7NH(CH2)3NHCH2C6H5), at 10-15 mg/kg i.p. three times per day for 3 days in combination with 2% alpha-difluoromethylornithine (DFMO; eflornithine) in drinking water effected cures of 47/54 mice infected with Plasmodium berghei. Cured mice were found to be immune upon rechallenge with the same P. berghei strain 4 months after the initial infection and drug-induced cure. MDL 27695 rapidly inhibited the incorporation of [3H]hypoxanthine into P. falciparum RNA and DNA, whereas the incorporation of [3H]isoleucine was not affected until much later. We conclude, therefore, that the major cytotoxic event may be direct binding of MDL 27695 to DNA with subsequent disruption of macromolecular biosynthesis and cell death. These compounds offer a lead in the search for new agents for chemotherapy of malaria. PMID:2463635

  10. Department of Humanities Department of Humanities

    E-print Network

    Heller, Barbara

    Department of Humanities Department of Humanities Program in Technology and the Humanities Siegel.iit.edu/csl/hum/programs/grad Chair: Maureen Flanagan, Department of Humanities Co-Directors, Graduate Studies: Matthew Bauer Karl Stolley gradhuminfo@iit.edu The Department of Humanities' Graduate Program in Technology and Humanities

  11. [Humanized childbirth].

    PubMed

    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. PMID:15986298

  12. Human torso

    NSDL National Science Digital Library

    William Cheselden (None; )

    2000-04-02

    The torso is the central area of the body that all the other body parts connect to. The ribcage contains the lungs and the heart. The intestines are located below them. The pelvic region contains the human reproductive parts and parts of the digestive and waste tracts.

  13. Human Impact

    NSDL National Science Digital Library

    Collection of nine classroom activities that focus on human impact on the environment. Topics include: oil spills; oil consumption; oil tanker size; greenhouse effect; salt water incursion; ozone hole and its affect on the food web; and zebra mussels. Each activity provides list of materials needed, background information, and procedure.

  14. Nothing Human

    ERIC Educational Resources Information Center

    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…

  15. Humanizing Calculus

    ERIC Educational Resources Information Center

    Cirillo, Michelle

    2007-01-01

    In this article, the author explores the history and the mathematics used by Newton and Leibniz in their invention of calculus. The exploration of this topic is intended to show students that mathematics is a human invention. Suggestions are made to help teachers incorporate the mathematics and the history into their own lessons. (Contains 3…

  16. Human Ectoparasites

    NSDL National Science Digital Library

    Sohmer, Rachel.

    Don't let the bedbugs bite! Actually, if you were to worry about all of the parasites living on your body (sometimes helping you out), you'd never fall asleep in the first place. As a living organism part of a bigger ecosystem, humans play host to unumerable other living things. This Topic In Depth offers a look into the fascinating world of Human Ectoparasites.The first stop -- a page from encyclopedia-style Web site InnVista -- offers a brief introduction to some of the ectoparasitic species that make their living off the human body (1). The next two sites contain science news articles courtesy of the Australian Broadcasting Corporation. The first article relates how the evolution of human body lice was made possible when we developed the habit of wearing clothes some 40,000 years ago (2). The second describes an alternative hypothesis as to why humans lost their fur. The University of Sydney and Westmead Hospital, Australia offers a quick introduction to the bedbug in the following Web site (4), while the University of Kentucky entomology department does the same for chiggers in the next (5). Kansas State University offers a few pictures and interesting tidbits on tooth amoebas, the toothbrush-fleeing microscopic parasites found where the teeth meet the gums (6). Don't worry, tooth amoebas are generally good for you. Another example of a beneficial ectoparasite is the leech, which is making a comeback in medical circles for its anticoagulant properties and other medicinal uses as related in an article from the BBC News (7). And finally, Duke University offers a intriguing introduction to eyebrow mites, benign parasites that live in our eyebrow follicles and are thus somewhat limited in their choice of mates (8).

  17. Differential expression of functional nucleoside transporters in non-differentiated and differentiated human endothelial progenitor cells.

    PubMed

    Guzmán-Gutiérrez, E; Sandoval, C; Nova, E; Castillo, J L; Vera, J C; Lamperti, L; Krause, B; Salomón, C; Sepúlveda, C; Aguayo, C; Sobrevia, L

    2010-10-01

    Extracellular adenosine removal is via human equilibrative nucleoside transporters 1 (hENT1) and 2 (hENT2) in the endothelium, thus regulating adenosine-induced revascularization and angiogenesis. Since human endothelial progenitor cells (hEPCs) promote revascularization, we hypothesize differential expression of nucleoside transporters in hEPCs. hEPCs were cultured 3 (hEPC-3d) or 14 (hEPC-14d) days. RT-PCR for prominin 1, CD34, octamer-4, kinase insert domain receptor, oxidized low-density lipoprotein (lectin-like) receptor 1 and tyrosine endothelial kinase was used to evaluate phenotypic differentiation. Flow cytometry was used to estimate CD34(+)/KDR(-) (non-differentiated), CD34(-)/KDR(+) (differentiated) or CD34(+)/KDR(+) (mixed) cell populations. Adenosine transport was measured in absence or presence of sodium, S-(4-nitrobenzyl)-6-thio-inosine (NBTI, 1-10 ?M), inosine, hypoxanthine or guanine (0.1-5 mM), hENTs protein abundance by western blot, and hENTs, hCNT1, hCNT2 and hCNT3 mRNA expression by real time RT-PCR. hEPC-3d cells were CD34(+)/KDR(-) compared with hEPC-14d cells that were CD34(-)/KDR(+). hEPC-3d cells exhibit hENT1-like adenosine transport (NBTI-sensitive, Na(+)-independent), which is absent in hEPC-14d cells. hEPC-14d cells exhibit two transport components: component 1 (NBTI insensitive, Na(+)-independent) and component 2 (NBTI insensitive, Na(+)-dependent, Hill coefficient ?1.8), the latter resembling CNT3-like transport. hEPC-3d cells express hENT1 protein and mRNA, which is reduced (?90%) in hEPC-14d cells, but instead only hCNT3 mRNA is expressed in this cell type. hENT2, hCNT1 and hCNT2 were undetectable in hEPCs. Thus, hEPCs exhibit a differential expression of hENT1 and hCNT3 functional nucleoside transporters, which could be related with its differentiation stage. PMID:20728214

  18. Human Rights in the Humanities

    ERIC Educational Resources Information Center

    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…

  19. Human Rights

    NSDL National Science Digital Library

    The idea of "human rights" is a relatively new development in history, but as this website from Britain's National Archives notes in its discussion of the long trajectory of struggles for equality and so forth, "We could do worse than characterizing this history as the struggle for human rights." This visually compelling online exhibit uses original documents from The National Archives to take a long view of these struggles and movements. Visitors can start their journey through the site by picking a time period, and then reading an introductory essay on the period. Each time period includes a timeline and links to digitized version of relevant documents, such as The Poor Act of 1601 and a poster for a Staffordshire coal miners' union public meeting from 1831. The site is rounded out by a thorough glossary and a document index.

  20. Human Anatomy

    NSDL National Science Digital Library

    This website, crafted by the State University of New York-Upstate Medical University, brings together key resources for students and others interested in human anatomy. These materials were designed with first year medical students in mind, but they will also be of use to individuals taking biology and other science-related courses. On the site, visitors can make their way through six sections ranging from extremities to the head and neck. Each area contains a variety of detailed anatomical charts, glossaries, and images. Radiology resources are also prominently featured within each section, providing students with a different perspective of the human body through x-rays, CT scans, and MRIs. Other helpful resources include fact sheets, quizzes, teaching materials, and other freely available course materials offered from other medical schools.

  1. Human mastication

    Microsoft Academic Search

    G. Slavicek

    2010-01-01

    Summary  Human mastication is a complex biomechanical process. Many different structures, tissues and functional units are involved.\\u000a The great variability observable in the procedures of crushing and lubricating food constrains the clear distinction between\\u000a physiologic and pathophysiologic chewing pattern. Diagnostic procedures on masticatory performance are still lacking clear\\u000a definitions and classifications. The use of individual chewing performance data in restorative dental

  2. Human Traits

    NSDL National Science Digital Library

    2012-06-26

    In this activity, learners investigate variations in human traits. This allows learners' natural curiosity about their identity to draw them into the study of heredity. Learners can investigate traits such as earlobe attachment, tongue rolling, hair and eye color, and hair texture. Through these traits, learners get an introduction to different inheritance patterns such as simple and incomplete dominance. Activity is usually done over multiple days to give learners time to survey people about their traits.

  3. Human genetics

    SciTech Connect

    Carlson, E.A.

    1984-01-01

    This text provides full and balanced coverage of the concepts requisite for a thorough understanding of human genetics. Applications to both the individual and society are integrated throughout the lively and personal narrative, and the essential principles of heredity are clearly presented to prepare students for informed participation in public controversies. High-interest, controversial topics, including recombinant DNA technology, oncogenes, embryo transfer, environmental mutagens and carcinogens, IQ testing, and eugenics encourage understanding of important social issues.

  4. Human Chromosomes

    NSDL National Science Digital Library

    BEGIN:VCARD VERSION:2.1 FN:Access Excellence N:Excellence; Access REV:2005-03-12 END:VCARD

    2005-03-12

    Representation of the 23 paired chromosomes of the human male. Chromosome: a very long DNA molecule and associated proteins, that carry portions of the hereditary information of an organism. a. Structure of a chromosome (Typical metaphase chromosome): A chromosome is formed from a single DNA molecule that contains many genes. A chromosomal DNA molecule contains three specific nucleotide sequences which are required for replication: a DNA replication origin; a centromere to attach the DNA to the mitotic spindle.; a telomere located at each end of the linear chromosome. The DNA molecule is highly condensed. The human DNA helix occupy too much space in the cell. Small proteins are responsible for packing the DNA into units called nucleosomes. b. Stained chromosomes: Chromosomes are stained with A-T (G bands) and G-C (R bands) base pair specific dyes. When they are stained, the mitotic chromosomes have a banded structure that unambiguously identifies each chromosome of a karyotype. Each band contains millions of DNA nucleotide pairs which do not correspond to any functional structure. Adapted from K.F. Jorgenson, J.H. van de Sande, and C.C. Lin, Chromosoma 68:287-302, 1978. c. Karyotype of a male: The human haploid genome contains 3,000,000,000 DNA nucleotide pairs, divided among twenty two (22) pairs of autosomes and one pair of sex chromosomes.

  5. Human Metapnemovirus (HMPV)

    MedlinePLUS

    ... Register for ENews Home > Lung Disease > Human Metapneumovirus Human Metapneumovirus Human metapneumovirus (hMPV) is a recently identified member of ... respiratory illnesses for at least 50 years worldwide. Human metapneumovirus can cause upper and lower respiratory tract ...

  6. Human Propulsion

    NSDL National Science Digital Library

    John Pratte

    This lesson points out that the motion of objects (velocity or acceleration) is almost never constant, and applies this idea to the motion of a person walking. The discussion covers the energy transfers involved in walking and in some other forms of human-powered transportation (crutches, bicycle, wheelchair), and the velocity and acceleration of an object that is moving in one dimension. The lesson includes an activity in which students use an accelerometer attached to a student volunteer to measure instantaneous acceleration in three dimensions, and calculate the total work which is done.

  7. [Human metapneumovirus].

    PubMed

    Kikuta, Hideaki

    2006-12-01

    Human metapneumovirus (hMPV), first isolated in the Netherlands in 2001, is a member of the genus Metapneumovirus of the sub-family Pneumovirinae of the family Paramyxoviridae. The genomic organization of hMPV is 3'-N-P-M-F-M2-SH-G-L-5'. hMPV resembles the sole member of this genus, avian pneumovirus. hMPV is the most closely related human pathogen to respiratory syncytial virus. Phylogenetic analysis of the nucleotide sequences indicated that there were two genetic groups. Furthermore, each group could be subdivided into two subgroups. hMPV encodes three surface proteins, F, G and SH proteins. The majority of antibodies to hMPV in serum were antibody against F protein, which mediates cross-group neutralization and protection. The incidences of hMPV-associated respiratory infection estimate 5 to 10% in children and 2 to 4% in adults. hMPV generally causes upper respiratory tract infection and flu-like illness, the virus can be associated with lower tract infections, such as wheezy bronchitis, bronchitis, bronchiolitis and pneumonia, in very young children, elderly persons, and immunocompromised patients. hMPV has a seasonal peak during the spring in Japan. Reinfection with hMPV frequently occurs in children, implying that the host immune response induced by natural infection provides incomplete protection. The RT-PCR test is the most sensitive test for detection of hMPV. PMID:17446666

  8. Human Subjects Section 6. Protection of Human

    E-print Network

    Heller, Barbara

    Human Subjects Section 6. Protection of Human Subjects This section is required for applicants answering "yes" to the question "Are human subjects involved?" on the R&R Other Project Information form. If the answer is "No" to the question but the proposed research involves human specimens and/or data from

  9. Building artificial humans to understand humans

    Microsoft Academic Search

    Hiroshi Ishiguro; Shuichi Nishio

    2007-01-01

    If we could build an android as a very humanlike robot, how would we humans distinguish a real human from an android? The\\u000a answer to this question is not so easy. In human–android interaction, we cannot see the internal mechanism of the android,\\u000a and thus we may simply believe that it is a human. This means that a human can

  10. Human monkeypox*

    PubMed Central

    Foster, Stanley O.; Brink, Edward W.; Hutchins, Deane L.; Pifer, John M.; Lourie, Bernard; Moser, Claude R.; Cummings, Evelyn C.; Kuteyi, O.E.K.; Eke, Reginald E. A.; Titus, J. B.; Smith, E. Ademola; Hicks, James W.; Foege, William H.

    1972-01-01

    Between October 1970 and May 1971, six cases of human infection with monkeypox virus were identified in Liberia, Nigeria, and Sierra Leone. Four of the cases were confirmed by virus isolation and two were diagnosed on the basis of epidemiological and serological investigations. All the cases occurred in unvaccinated individuals. Post-infection serological studies showed high haemagglutination-inhibition and neutralizing titres to pox group virus in four of the cases. Repeated challenge vaccination of all cases with potent smallpox vaccine resulted in equivocal reactions. In all, 24 susceptible household contacts were exposed to the infected cases, but none developed disease. All the contacts subsequently responded to vaccination with a primary reaction, thus confirming their susceptibility and ruling out asymptomatic infection. ImagesFig. 1Fig. 2Fig. 3 PMID:4340216

  11. Human Factors in Human-Systems Integration

    NASA Technical Reports Server (NTRS)

    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.

  12. integration division Human Systems

    E-print Network

    future air traffic management (ATM) systems and associated human-system interactions. One of the mainintegration division Human Systems Exploration of Human Systems Integration Issues in Next to understand potential human performance and human- system interactions issues related to NextGen concepts

  13. Xanthine metabolism in Bacillus subtilis: characterization of the xpt-pbuX operon and evidence for purine- and nitrogen-controlled expression of genes involved in xanthine salvage and catabolism.

    PubMed Central

    Christiansen, L C; Schou, S; Nygaard, P; Saxild, H H

    1997-01-01

    The xpt and pbuX genes from Bacillus subtilis were cloned, and their nucleotide sequences were determined. The xpt gene encodes a specific xanthine phosphoribosyltransferase, and the pbuX gene encodes a xanthine-specific purine permease. The genes have overlapping coding regions, and Northern (RNA) blot analysis indicated an operon organization. The translation of the second gene, pbuX, was strongly dependent on the translation of the first gene, xpt. Expression of the operon was repressed by purines, and the effector molecules appear to be hypoxanthine and guanine. When hypoxanthine and guanine were added together, a 160-fold repression was observed. The regulation of expression was at the level of transcription, and we propose that a transcription termination-antitermination control mechanism similar to the one suggested for the regulation of the purine biosynthesis operon exists. The expression of the xpt-pbuX operon was reduced when hypoxanthine served as the sole nitrogen source. Under these conditions, the level of the hypoxanthine- and xanthine-degrading enzyme, xanthine dehydrogenase, was induced more than 80-fold. The xanthine dehydrogenase level was completely derepressed in a glnA (glutamine synthetase) genetic background. Although the regulation of the expression of the xpt-pbuX operon was found to be affected by the nitrogen source, it was normal in a glnA mutant strain. This result suggests the existence of different signalling pathways for repression of the transcription of the xpt-pbuX operon and the induction of xanthine dehydrogenase. PMID:9098051

  14. Human herpesvirus 8 – A novel human pathogen

    PubMed Central

    Edelman, Daniel C

    2005-01-01

    In 1994, Chang and Moore reported on the latest of the gammaherpesviruses to infect humans, human herpesvirus 8 (HHV-8) [1]. This novel herpesvirus has and continues to present challenges to define its scope of involvement in human disease. In this review, aspects of HHV-8 infection are discussed, such as, the human immune response, viral pathogenesis and transmission, viral disease entities, and the virus's epidemiology with an emphasis on HHV-8 diagnostics. PMID:16138925

  15. Engineered human vaccines

    SciTech Connect

    Sandhu, J.S. (Mount Sinai Hospital, Toronto, Ontario (Canada). Div. of Immunology and Neurobiology)

    1994-01-01

    The limitations of human vaccines in use at present and the design requirements for a new generation of human vaccines are discussed. The progress in engineering of human vaccines for bacteria, viruses, parasites, and cancer is reviewed, and the data from human studies with the engineered vaccines are discussed, especially for cancer and AIDS vaccines. The final section of the review deals with the possible future developments in the field of engineered human vaccines and the requirement for effective new human adjuvants.

  16. Human-machine interactions

    DOEpatents

    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. Human retroviruses.

    PubMed

    Weber, T; Hunsmann, G; Stevens, W; Fleming, A F

    1992-04-01

    It was only in 1980 that the first human retrovirus, HTLV-1, was isolated. Since then, HTLV-2, HIV-1 and HIV-2 have been identified. All four viruses are transmitted with varying efficiency sexually, vertically from mother to infant, and through blood by transfusion or contamination. HTLV-1 is endemic in populations in south-west Japan, Taiwan, sub-Saharan Africa, the Caribbean, southern USA, central and south America, Australia, Papua New Guinea, Solomon Islands and western Asia. There is now epidemic spread amongst IVDUs in north and south America and southern Europe. HTLV-1 is the aetiological agent of adult T-cell leukaemia/lymphoma (ATL) and tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM). Other associations which may be causative are with polymyositis, infective dermatitis, gastrointestinal malignant lymphoma and chronic lymphatic leukaemia. ATL appears to be due to malignant transformation of HTLV-1 infected cells, and TSP/HAM to chronic activation of these cells. The epidemiology of HTLV-2 is being separated only recently from HTLV-1 through the application of PCR. It has a low level of endemicity in populations of central Africa, and central and south America. It is being spread epidemically amongst IVDUs in north America and southern Europe. Its association with any pathology in man remains uncertain. HIV-1 is epidemic and spreading rapidly throughout the world. In areas where homosexual contact was the predominant mode of transmission, heterosexual spread is becoming increasingly important. The areas where heterosexual contact is the predominant mode of transmission include the worst affected populations in the world, for example sub-Saharan Africa and some of the Caribbean. There have been recent and explosive increases of HIV-1 seroprevalence in IVDUs and female prostitutes in Asia, especially Thailand and India. Of the diverse pathology following infection, only the haematological consequences are reviewed in detail: these include anaemia, leucopenia, thrombocytopenia, disorders of coagulation and lymphomas. HIV-2, compared to HIV-1, is less infectious and causes less immunosuppression with more slowly progressive disease. It is prevalent in west Africa, but is spreading, albeit slowly, far beyond. PMID:1324749

  18. Virtual Human Project

    Microsoft Academic Search

    R. C. Ward; K. L. Kruse; G. O. Allgood; L. M. Hively; K. N. Fischer; N. B. Munro; C. E. Easterly

    This paper describes the development of a comprehensive human modeling environment, the Virtual Human, which will be used initially to model the human respiratory system for purposes of predicting pulmonary disease or injury using lung sounds. The details of the computational environment, including the development of a V irtual Human Thorax, a database for storing models, model parameters, and experimental

  19. Visualizing Humans by Computer.

    ERIC Educational Resources Information Center

    Magnenat-Thalmann, Nadia

    1992-01-01

    Presents an overview of the problems and techniques involved in visualizing humans in a three-dimensional scene. Topics discussed include human shape modeling, including shape creation and deformation; human motion control, including facial animation and interaction with synthetic actors; and human rendering and clothing, including textures and…

  20. Human Computer Intelligent Interaction

    E-print Network

    Chen, Sheng-Wei

    Human Computer Intelligent Interaction Computer technologies are progressing at a breakneck speed doing during the last decade on Human Computer Interaction. Specifically,information flow from human human-computer interfaces.In this talk,I shall describe some of the research my students and I have been

  1. The Humanities: Interconnections.

    ERIC Educational Resources Information Center

    Salomone, Ronald E., Ed.

    1985-01-01

    Focusing on a wide range of interdisciplinary themes and ideas for humanities instruction, the 17 articles in this journal issue discuss the following topics: (1) literature, humanities, and the adult learner; (2) the role of the humanities in educating for a democracy; (3) humanities in the marketplace; (4) literature versus "great books" in high…

  2. Humanities 1 Department of

    E-print Network

    Humanities 1 Department of --Humanities This publication refers to the session 2009 of postgraduate opportunities go to www.imperial.ac.uk/pgprospectus. #12;2 Undergraduate syllabuses Humanities Teaching in Humanities at Imperial College London at undergraduate level is focused on service modules

  3. Cellular resistance and hypermutability in mismatch repair-deficient human cancer cell lines following treatment with methyl methanesulfonate

    Microsoft Academic Search

    Warren E Glaab; John I Risinger; Asad Umar; J. Carl Barrett; Thomas A Kunkel; Kenneth R Tindall

    1998-01-01

    Resistance to the cytotoxic effects of SN1 alkylating agents such as N-methyl-N?-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitrosourea (MNU) is well established in mismatch repair-defective cells, however, little is known about the cellular response to SN2 alkylating agents in these cells. Here we describe the cytotoxic response and the mutagenic response at the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus to the SN2 alkylating agent

  4. Cell differentiation and altered IMP dehydrogenase expression induced in human T-lymphoblastoid leukemia cells by mycophenolic acid and tiazofurin

    Microsoft Academic Search

    K. Kiguchi; F. R. Collart; C. Henning-Chubb; E. Huberman

    1990-01-01

    The IMP dehydrogenase inhibitors mycophenolic acid (MPA) and tiazofurin (TZ) induce a time- and dose-dependent inhibition of cell growth, as well as differentiation in T-lymphoid CEM-2 leukemia cells. The differentiated cells have acquired a suppressor\\/cytotoxic T-lymphocyte phenotype characterized by reactivity with maturation-specific monoclonal antibodies. Coadministration of guanosine and hypoxanthine reduces the growth inhibition and diminishes the induction of differentiation by

  5. DIGITAL_HUMANITIES DIGITAL_HUMANITIES

    E-print Network

    #12;DIGITAL_HUMANITIES #12;#12;DIGITAL_HUMANITIES ANNE BURDICK JOHANNA DRUCKER PETER LUNENFELD TODD-in-Publication Data Digital_humanities / Anne Burdick ... [et al.]. p. cm. ISBN 978-0-262-01847-0 (hardcover : alk. Burdick, Anne. AZ195.D54 2012 001.30285--dc23 2012026514 10 9 8 7 6 5 4 3 2 1 #12;PRefACe vii 1

  6. Mice with human livers.

    PubMed

    Grompe, Markus; Strom, Stephen

    2013-12-01

    Animal models are used to study many aspects of human disease and to test therapeutic interventions. However, some very important features of human biology cannot be replicated in animals, even in nonhuman primates or transgenic rodents engineered with human genes. Most human microbial pathogens do not infect animals and the metabolism of many xenobiotics is different between human beings and animals. The advent of transgenic immune-deficient mice has made it possible to generate chimeric animals harboring human tissues and cells, including hepatocytes. The liver plays a central role in many human-specific biological processes and mice with humanized livers can be used to model human metabolism, liver injury, gene regulation, drug toxicity, and hepatotropic infections. PMID:24042096

  7. Designing human friendly human interaction proofs (HIPs)

    Microsoft Academic Search

    Kumar Chellapilla; Kevin Larson; Patrice Y. Simard; Mary Czerwinski

    2005-01-01

    HIPs, or Human Interactive Proofs, are challenges meant to be easily solved by humans, while remaining too hard to be economically solved by computers. HIPs are increasingly used to protect services against automatic script attacks. To be effective, a HIP must be difficult enough to discourage script attacks by raising the computation and\\/or development cost of breaking the HIP to

  8. Climate and Human Evolution

    NSDL National Science Digital Library

    2010-09-22

    In this video segment adapted from NOVA: Becoming Human, learn how the analysis of rock layers and ocean sediments supports the theory that rapid climate change may have jump-started human evolution two million years ago.

  9. Pathfinder: Humans in space

    NASA Technical Reports Server (NTRS)

    Anderson, John L.

    1988-01-01

    Viewgraphs are presented on the Pathfinder program. Information is given on human exploration of the solar system, technical requirements interfaces, program objectives, space suits, human performance, man-machine systems, space habitats, life support systems, and artificial gravity

  10. Human bites (image)

    MedlinePLUS

    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.

  11. Statement on Human Cloning

    MedlinePLUS

    ... Association for the Advancement of Science Statement on Human Cloning Tweet Email Print The American Association for the ... debates within our society on the issue of human cloning. Since 1997, AAAS has engaged the public and ...

  12. Telling the Human Story.

    ERIC Educational Resources Information Center

    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)

  13. Studies That Observe Humans

    MedlinePLUS

    ... Topic Human testing: Clinical trials Studies that observe humans A study that simply looks at people is ... in the past without counting on a person’s memory. And there’s no way to find out what ...

  14. Human Specimen Resources | Resources

    Cancer.gov

    Researchers who utilize or require human specimens for their research may benefit from the information in this section, including how to find specimens for research, how to establish a tissue bank or resource, and funding opportunities related to human specimens.

  15. Mining human antibody repertoires

    PubMed Central

    2010-01-01

    Human monoclonal antibodies (mAbs) have become drugs of choice for the management of an increasing number of human diseases. Human antibody repertoires provide a rich source for human mAbs. Here we review the characteristics of natural and non-natural human antibody repertoires and their mining with non-combinatorial and combinatorial strategies. In particular, we discuss the selection of human mAbs from naïve, immune, transgenic and synthetic human antibody repertoires using methods based on hybridoma technology, clonal expansion of peripheral B cells, single-cell PCR, phage display, yeast display and mammalian cell display. Our reliance on different strategies is shifting as we gain experience and refine methods to the efficient generation of human mAbs with superior pharmacokinetic and pharmacodynamic properties. PMID:20505349

  16. HUMAN RESOURCES CAREER DEVELOPMENT

    E-print Network

    Subramanian, Venkat

    HUMAN RESOURCES CAREER DEVELOPMENT COMPETENCY FACTORS TABLE OF CONTENTS ABILITY TO ANALYZE & LEARN ............ ............ ............ ............ ............ ............ ............ ............2 CREATIVITY / INNOVATION ..... ............ ............ ............ ............ ............ ............ ............ ............ ............ ............10 ORAL COMMUNICATION

  17. Human centromeric DNAs

    Microsoft Academic Search

    C. Lee; R. Wevrick; R. B. Fisher; M. A. Ferguson-Smith; C. C. Lin

    1997-01-01

    Human centromeres have been extensively studied over the past two decades. Consequently, more is known of centromere structure\\u000a and organization in humans than in any other higher eukaryote species. Recent advances in the construction of a human (or\\u000a mammalian) artificial chromosome have fostered increased interest in determining the structure and function of fully functional\\u000a human centromeres. Here, we present an

  18. Demystifying the Humanities.

    ERIC Educational Resources Information Center

    Bonham, George

    1980-01-01

    The new Rockefeller Foundation's Commission on the Humanities' report is discussed. Some of the commission's recommendations include: improved quality of elementary and secondary schools, strengthening of humanities research, reaffirmation within education of the values of the humanities, and closer collaboration of educational and cultural…

  19. Dogs catch human yawns

    Microsoft Academic Search

    Ramiro M. Joly-Mascheroni; Atsushi Senju; Alex J. Shepherd

    2008-01-01

    Summary This study is the first to demonstrate that human yawns are possibly contagious to domestic dogs (Canis familiaris). Twenty-nine dogs observed a human yawning or making control mouth movements. Twenty-one dogs yawned when they observed a human yawning, but control mouth movements did not elicit yawning from any of them. The presence of contagious yawning in dogs suggests that

  20. Human nature and enhancement.

    PubMed

    Buchanan, Allen

    2009-03-01

    Appeals to the idea of human nature are frequent in the voluminous literature on the ethics of enhancing human beings through biotechnology. Two chief concerns about the impact of enhancements on human nature have been voiced. The first is that enhancement may alter or destroy human nature. The second is that if enhancement alters or destroys human nature, this will undercut our ability to ascertain the good because, for us, the good is determined by our nature. The first concern assumes that altering or destroying human nature is in itself a bad thing. The second concern assumes that human nature provides a standard without which we cannot make coherent, defensible judgments about what is good. I will argue (1) that there is nothing wrong, per se, with altering or destroying human nature, because, on a plausible understanding of what human nature is, it contains bad as well as good characteristics and there is no reason to believe that eliminating some of the bad would so imperil the good as to make the elimination of the bad impermissible, and (2) that altering or destroying human nature need not result in the loss of our ability to make judgments about the good, because we possess a conception of the good by which we can and do evaluate human nature. I will argue that appeals to human nature tend to obscure rather than illuminate the debate over the ethics of enhancement and can be eliminated in favor of more cogent considerations. PMID:19161567

  1. Developments in Human Communication

    E-print Network

    Haykin, Simon

    CMST 1B03 Developments in Human Communication: Part & Present Amanda Etches-Johnson Mills Research in Human Communication Session Outline 1. Finding Books Using MORRIS 2. Finding Journal Articles using: Developments in Human Communication What is MORRIS anyway? · MORRIS is McMaster's library catalogue · Shows

  2. Visible Human Project

    MedlinePLUS

    ... Mirror Sites Tools Media Productions Related Projects The Visible Human Project ® Overview The Visible Human Project ® is an outgrowth of the NLM's 1986 ... millimeter intervals. The long-term goal of the Visible Human Project ® is to produce a system of knowledge ...

  3. The Humanities' Value

    ERIC Educational Resources Information Center

    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…

  4. Human Rights and Security

    E-print Network

    Jones, Peter JS

    Migration, Human Rights and Security in Europe MRU Student Conference Proceedings 2012 Edited by Siril Berglund, Helen McCarthy and Agata Patyna #12;2 "Migration, Human Rights and Security...............................................................................................58 #12;3 "Migration, Human Rights and Security in Europe", MRU Student Conference Proceedings

  5. Humanities 4 Professor Watkins

    E-print Network

    Blanco, Philip R.

    Humanities 4 Professor Watkins Winter 2013 Writing Assignment No. 1 Essays are due at the beginning) in the Humanities format* and a counterargument is required. Respond to one of the following prompts: 1. Write in a manila folder with your name on it and containing your previous Humanities essays. Late essays

  6. Humanities 1 Professor Edwards

    E-print Network

    Blanco, Philip R.

    Humanities 1 Professor Edwards Winter 2013 Writing Exercise Assignments are due at the end of lecture on Wednesday, January 16th . They should be 1-2 pages in length in the Humanities format (see in a plain manila folder with your name on it. All Humanities essays are to be saved and turned in each time

  7. Secure distributed human computation

    Microsoft Academic Search

    Craig Gentry; Zulfikar Ramzan; Stuart Stubblebine

    2005-01-01

    This paper is a preliminary exploration of secure distributed human computation. We consider the general paradigm of using large-scale distributed computation to solve difficult problems, but where humans can act as agents and provide candidate solutions. We are especially motivated by problem classes that appear to be difficult for computers to solve effectively, but are easier for humans; e.g., image

  8. Portraits of Human Greatness.

    ERIC Educational Resources Information Center

    Saint Anselm's Coll., Manchester, NH.

    Examined is the Humanities Program at St. Anselm College, a two-year program of readings and lectures ordered chronologically from ancient to contemporary times--from the age of Classical Greek thought and the Old Testament to the twentieth century. The first year of the Humanities Program is organized in eight units on general modes of "human…

  9. HUMAN EXPOSURE ACTIVITY PATTERNS

    EPA Science Inventory

    Human activity/uptake rate data are necessary to estimate potential human exposure and intake dose to environmental pollutants and to refine human exposure models. Personal exposure monitoring studies have demonstrated the critical role that activities play in explaining and pre...

  10. DEPARTMENT OF HUMAN RESOURCES

    E-print Network

    Brownstone, Rob

    DEPARTMENT OF HUMAN RESOURCES JULY 1, 2010 ­ JUNE 30, 2013 STRATEGIC PLAN #12;Page 1 Introduction Human resource strategies are institutional efforts to support people (leaders, faculty and staff. Well executed human resource strategies bring success to individuals, teams, work units and ultimately

  11. Faculty Affairs, Human Resources

    E-print Network

    Finley Jr., Russell L.

    Office Of Faculty Affairs, Human Resources and Professional Development Welcome to Wayne: SOM New/Information Fair · Research Environment · Career Development #12;Office Of Faculty Affairs, Human Resources;Office Of Faculty Affairs, Human Resources and Professional Development Objectives Share information

  12. Physical Collaboration of Human-Human and Human-Robot Teams

    E-print Network

    Ottino, Julio M.

    Physical Collaboration of Human-Human and Human-Robot Teams Kyle B. Reed, Member, IEEE, and Michael of human haptic communication, we attempted a "Haptic Turing Test," replicating human behaviors in a robot, human-machine, human-robot interaction, physical cooperation, collaboration, pHRI. Ç 1 INTRODUCTION

  13. Human milk and human milk fortifiers.

    PubMed

    Ziegler, Ekhard E

    2014-01-01

    Human milk contains numerous immune-protective components that protect the premature infant from sepsis and necrotizing enterocolitis. Because of these protective effects, human milk is the feeding of choice for the premature infant. However, human milk does not provide adequate amounts of most nutrients for premature infants and must therefore be supplemented (fortified) with nutrients. Commercially available fortifiers provide energy and most nutrients in adequate amounts. The exception is protein, which is present in expressed milk in highly variable amounts and which is not provided in sufficient amounts by most fortifiers. Some liquid fortifiers are higher in protein content than powder fortifiers and provide adequate amounts of protein. PMID:24751632

  14. Rethinking medical humanities.

    PubMed

    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. PMID:24477428

  15. Human Mitochondrial Protein Database

    National Institute of Standards and Technology Data Gateway

    SRD 131 Human Mitochondrial Protein Database (Web, free access)   The Human Mitochondrial Protein Database (HMPDb) provides comprehensive data on mitochondrial and human nuclear encoded proteins involved in mitochondrial biogenesis and function. This database consolidates information from SwissProt, LocusLink, Protein Data Bank (PDB), GenBank, Genome Database (GDB), Online Mendelian Inheritance in Man (OMIM), Human Mitochondrial Genome Database (mtDB), MITOMAP, Neuromuscular Disease Center and Human 2-D PAGE Databases. This database is intended as a tool not only to aid in studying the mitochondrion but in studying the associated diseases.

  16. Human-technology Integration

    NASA Astrophysics Data System (ADS)

    Mullen, Katharine M.

    Human-technology integration is the replacement of human parts and extension of human capabilities with engineered devices and substrates. Its result is hybrid biological-artificial systems. We discuss here four categories of products furthering human-technology integration: wearable computers, pervasive computing environments, engineered tissues and organs, and prosthetics, and introduce examples of currently realized systems in each category. We then note that realization of a completely artificial sytem via the path of human-technology integration presents the prospect of empirical confirmation of an aware artificially embodied system.

  17. Human Rights Library

    NSDL National Science Digital Library

    The Human Rights Library of the University of Minnesota holds a collection of over ninety of the most important international human rights instruments -- treaties, declarations, and other materials -- together with authoritative citations. The documents are easily accessed by subject matter or searched by keyword. In addition, the site offers information about the work of the human rights treaty bodies, including general comments and recommendations, decisions and views of the U.N. Human Rights Committee, and other materials. Links to other useful sites containing information about human rights and relevant resources are also provided.

  18. Biological effectiveness of nuclear fragments produced by high-energy protons interacting in tissues near the bone- soft tissue interface

    NASA Astrophysics Data System (ADS)

    Shavers, Mark Randall

    1999-12-01

    High-energy protons in the galactic cosmic rays (GCR)-or generated by nuclear interactions of GCR heavy-ions with material-are capable of penetrating great thicknesses of shielding to irradiate humans in spacecraft or in lunar or Martian habitats. As protons interact with the nuclei of the elemental constituents of soft tissue and bone, low energy nuclei-target fragments-are emitted into the cells responsible for bone development and maintenance and for hematopoiesis. Leukemogenesis is the principal endpoint of concern because it is the most likely deleterious effect, and it has a short latency period and comparatively low survival rate, although other myelo- proliferative disorders and osteosarcoma also may be induced. A one-dimensional proton-target fragment transport model was used to calculate the energy spectra of fragments produced in bone and soft tissue, and present in marrow cavities at distances from a bone interface. In terms of dose equivalent, the target fragments are as significant as the incident protons. An average radiation quality factor was found to be between 1.8 and 2.6. Biological response to the highly non- uniform energy deposition of the target fragments is such that an alternative approach to conventional predictive risk assessment is needed. Alternative procedures are presented. In vitro cell response and relative biological effectiveness were calculated from the radial dose distribution of each fragment produced by 1-GeV protons using parameters of a modified Ion-Gamma- Kill (IGK) model of radiation action. The modelled endpoints were survival of C3H10t 1/2 and V79 cells, neoplastic transformation of C3H10t1/2 cells, and mutation of the X-linked hypoxanthine phosphoribosyltransferase (HPRT) locus in V79 cells. The dose equivalent and cell responses increased by 10% or less near the interface. Since RBE increases with decreasing dose in the IGK model, comparisons with quality factors were made at dose levels 0.01 <= D [Gy] <= 2. Applying average quality factors derived herein to GCR exposures results in a <= 5% increase of in average quality. Calculated RBEs indicate that accepted quality factors for high-energy protons may be too low due to the relatively high effectiveness of the low-charged target fragments. Derived RBEs for target fragments increase the calculated biological effectiveness of GCR by 20% to 180%.

  19. Biomarkers and human hepatocytes.

    PubMed

    Li, Albert P

    2014-01-01

    The accuracy of preclinical safety evaluation to predict human toxicity is hindered by species difference in drug metabolism and toxic mechanism between human and nonhuman animals. In vitro human-based experimental systems allowing the assessment of human-specific drug properties represent a logical and practical approach to provide human-specific information. An advantage of in vitro approaches is that they require only limited amounts of time and resources, and, most importantly, do not invoke harm to human patients. Human hepatocytes, with complete hepatic metabolizing enzymes, transporters and cofactors, represent a practical and useful experimental system to assess drug metabolism. The use of human hepatocytes to evaluate two major adverse drug properties, drug-drug interactions and hepatotoxicity, are reviewed. The application of human hepatocytes in metabolism-based drug-drug interactions includes metabolite profiling, pathway identification, CYP450 inhibition, CYP450 induction, and uptake and efflux transporter inhibition. The application of human hepatocytes in toxicity evaluation includes in vitro hepatotoxicity and metabolism-based drug toxicity determination. Correlation of drug toxicity with proteomics and genomics data may allow the discovery of clinical biomarkers for early detection of liver toxicity. PMID:24521013

  20. Human-human vs. human-robot teamed investigation

    Microsoft Academic Search

    Caroline E. Harriott; Glenna L. Buford; Tao Zhang; Julie A. Adams

    2012-01-01

    Clips from an evaluation where participants, each paired with either a human or robot partner, were deployed to search a hallway for suspicious items, in a manner similar to tactics used by first responders handling bomb threats are presented. The teams used natural, verbal communication to collaborate, determine where hazards were located, and which items were suspicious. The video demonstrates

  1. Human Performance in Space

    NASA Technical Reports Server (NTRS)

    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.

  2. Human reliability analysis

    SciTech Connect

    Dougherty, E.M.; Fragola, J.R.

    1988-01-01

    The authors present a treatment of human reliability analysis incorporating an introduction to probabilistic risk assessment for nuclear power generating stations. They treat the subject according to the framework established for general systems theory. Draws upon reliability analysis, psychology, human factors engineering, and statistics, integrating elements of these fields within a systems framework. Provides a history of human reliability analysis, and includes examples of the application of the systems approach.

  3. Secure Distributed Human Computation

    Microsoft Academic Search

    Craig Gentry; Zulfikar Ramzan; Stuart G. Stubblebine

    2006-01-01

    Abstract. This paper introduces a line of research on secure distributed human,computation. We consider the general paradigm of using large-scale distributed computation to solve di?cult problems, but where humans,can act as agents and provide candidate solutions. We are especially motivated by problem classes that appear to be di?cult for computers to solve efiectively, but are easier for humans to solve;

  4. Annotated Webliography Of Humanism

    NSDL National Science Digital Library

    Derkx, Peter.

    Created and maintained by Peter Derkx, a professor of history at the University for Humanist Studies, this Website offers a useful directory of annotated links on the subject of humanism from its inception in the Renaissance to its current struggles with Marxism and Postmodernism. The selections when addressing more contemporary topics often deal with humanism only indirectly -- a sign perhaps of the failing interest in humanism per se, rather than any lack of diligence on Dr. Derkx' part.

  5. Human Genome Resources

    NSDL National Science Digital Library

    In an effort to track the progress of and provide access to the work of the Human Genome Project (see the October 14, 1998 Scout Report for Science & Engineering), the National Center for Biotechnology Information (NCBI) of the National Library of Medicine (NLM) has expanded their Web resource. An international research program "designed to construct detailed genetic and physical maps of the human genome." The Human Genome Resources page provides a wealth of relevant resources, from background information on the project, to specific sequences for each human chromosome (click on the desired chromosome), to Genome Maps of other organisms.

  6. Artificial human vision camera

    NASA Astrophysics Data System (ADS)

    Goudou, J.-F.; Maggio, S.; Fagno, M.

    2014-10-01

    In this paper we present a real-time vision system modeling the human vision system. Our purpose is to inspire from human vision bio-mechanics to improve robotic capabilities for tasks such as objects detection and tracking. This work describes first the bio-mechanical discrepancies between human vision and classic cameras and the retinal processing stage that takes place in the eye, before the optic nerve. The second part describes our implementation of these principles on a 3-camera optical, mechanical and software model of the human eyes and associated bio-inspired attention model.

  7. Developing Human Resources through Actualizing Human Potential

    ERIC Educational Resources Information Center

    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,…

  8. Methods in human cytogenetics

    SciTech Connect

    NONE

    1993-12-31

    Chapter 4, discusses the various techniques used in the study human cytogenetics. The methods are discussed in historical order, from direct methods to tissue culture techniques, prenatal studies, meiotic studies, sex chromatin techniques, banding techniques, prophase banding and replication studies. Nomenclature of human chromosomes and quantitative methods are also mentioned. 60 refs., 3 figs.

  9. Human Development and Sustainability

    Microsoft Academic Search

    Eric Neumayer

    2012-01-01

    This article reviews existing linkages between the two broad concepts of human development and sustainability and discusses ways in which the often separate literatures can learn from each other. It proposes a practical way in which the measurements of human development and sustainability can be linked with each other. Empirical results for both a weak and a strong sustainability indicator

  10. Hooking Kids with Humanities.

    ERIC Educational Resources Information Center

    Anstead, Neil L.

    1993-01-01

    Humanitas is part of Collaboratives for Humanities and Arts Teaching (CHART), a nationwide network funded primarily by the Rockefeller Foundation. In 11 large school districts and numerous rural districts, high school teachers, academics, artists, and business and community leaders are cooperating to promote teaching of the arts and humanities

  11. Strengthening Career Human Agency

    ERIC Educational Resources Information Center

    Chen, Charles P.

    2006-01-01

    Rooted in A. Bandura's (1982, 2001b) social cognitive theory, the notion of human agency has received considerable attention in vocational and career psychology for the last 2 decades, especially with the recent emergence of social constructivist thinking in the field. This article continues in the same direction. In reviewing the notion of human…

  12. Healthline Human Body Maps

    NSDL National Science Digital Library

    Healthline (Healthline Networks Inc)

    2005-01-01

    This website provides a 3-D animation of the human body. The animation allows visitors to view a variety of layers of the human body organized by both system and organs. In addition, health information, articles, and structures can be found with each layer. The website is also searchable by specific structure.

  13. Caloric restriction in humans

    Microsoft Academic Search

    John O. Holloszy; Luigi Fontana

    2007-01-01

    Studies on mice and rats have demonstrated that calorie restriction (CR) slows primary aging, has a protective effect against secondary aging, and markedly decreases the incidence of malignancies. However, the only way to determine whether CR “works” in humans is to conduct studies on people. Such studies are difficult to perform in free-living people. While research on CR in humans

  14. Aesthetics and Human Rights

    Microsoft Academic Search

    Winston P. Nagan; Aitza M. Haddad

    2012-01-01

    This article seeks to contribute to a better understating of the relationship between aesthetics and fundamental human rights. The initial challenge was to develop a more clarified conception of aesthetics as a social process in order to better mark those aspects of aesthetics that have clear human rights implications. This required us to contextualize the aesthetics process in terms of

  15. Humanism: A Theoretical Perspective.

    ERIC Educational Resources Information Center

    Alam, Dale V.

    1983-01-01

    Argues that behaviorism and humanism are incompatible, and any attempt to blend them is to deny the intellectual or practical existence of humanism as a theory of behavior. Humanistic theory must be recognized and application models must be designed and tested in school, childrearing, personal relations and leadership theory. (JAC)

  16. Virtual Human Anatomy

    Microsoft Academic Search

    Lin Yong; J. X. Chen; Yanling Liu

    2005-01-01

    To learn human anatomy, medical students must practice on cadavers, as must physicians when they want to brush up on their anatomy knowledge. However, cadavers are in short supply in medical schools worldwide. One potential solution to this problem is the virtual human anatomy and surgery system. VHASS uses cryosection images - cross-section natural-color images generated by slicing a frozen

  17. Human Sociobiology: Wilson's Fallacy.

    ERIC Educational Resources Information Center

    Lehrman, Nathaniel S.

    1981-01-01

    Presents an introduction to and a critique of E.O. Wilson's new science of sociobiology, which focuses on explaining the social behavior of species as diverse as ants, apes, and humans. Suggests that Wilson has gone beyond his data in claiming that complex human behaviors such as altruism are caused to any extent by genetic, as opposed to…

  18. Human Water Cycle

    NSDL National Science Digital Library

    2014-09-18

    Students learn about the human water cycle, or how humans impact the water cycle by settling down in civilizations. Specifically, they learn how people obtain, use and dispose of water. Students also learn about shortages of treated, clean and safe water and learn about ways that engineers address this issue through water conservation and graywater recycling.

  19. Immunology Taught by Humans

    PubMed Central

    Davis, Mark M.

    2013-01-01

    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. PMID:22261029

  20. The human genome project

    Microsoft Academic Search

    Thomas D. Yager; Thomas E. Zewert; Leroy E. Hood

    1994-01-01

    The Human Genome Project (HGP) is a coordinated worldwide effort to precisely map the human genome and the genomes of selected model organisms. The first explicit proposal for this project dates from 1985 although its foundations (both conceptual and technological) can be traced back many years in genetics, molecular biology, and biotechnology. The HGP has matured rapidly and is producing

  1. Future Evolution of Humanity

    Microsoft Academic Search

    Linda Groff

    2007-01-01

    The future evolution of humanity is a huge topic. There are a number of factors that will influence the future evolution of humanity, including how people view and deal with change in general; different models of the processes of evolution and change transforming our world, and different substantive stages of evolution - in physical, biological, cultural, technological, and consciousness areas

  2. Humanities 1 Winter 2013

    E-print Network

    Blanco, Philip R.

    of these tests tend to show that human beings are not made in the image of God; they aren't smart enoughHumanities 1 Winter 2013 Professor Cox Writing Assignment No. 2 (first graded assignment) Select as you can. 2. "In Genesis and Exodus 1-23, men and women are frequently subjected to tests. The outcomes

  3. HEALTH AND HUMAN RIGHTS

    Microsoft Academic Search

    Jonathan M. Mann; Sofia Gruskin; MIA Troyen Brennan; Harvey V Fineberg

    1994-01-01

    H ealth and human rights have rarely been linked in an ex- plicit manner. With few exceptions, notably involving access to health care, discussions about health have rarely.included hu- man rights considerations. Similarly, except when obvious dam- age to health is the primary manifestation of a human rights abuse, such as with torture, health perspectives have been gen- erally absent

  4. Human Rights in Education

    E-print Network

    Ellis, Randy

    1 Human Rights in Education European View on Childhood and Education . .3 Children's Rights for several decades. The Canadian Bill of Rights (1960) and the federal and provincial human rights in Competitive Sport . . . . . . . . .4 Equality Rights of the Child . . . . . . . . . . . . . . .6 Resources

  5. Humanism within Globalization

    ERIC Educational Resources Information Center

    Weber, Jennifer E.

    2014-01-01

    The complexity of adult learning connects it to almost all other facets of human endeavor. Consequently, the future of adult education depends, to a large extent on who participates and the quality of such participation. Quality participation, when teamed with environments committed to a concern for humanity, launches opportunities for varied…

  6. Human Powered Centrifuge

    NASA Technical Reports Server (NTRS)

    Mulenburg, Gerald M. (Inventor); Vernikos, Joan (Inventor)

    1997-01-01

    A human powered centrifuge has independently established turntable angular velocity and human power input. A control system allows excess input power to be stored as electric energy in a battery or dissipated as heat through a resistors. In a mechanical embodiment, the excess power is dissipated in a friction brake.

  7. Secure Distributed Human Computation

    Microsoft Academic Search

    Craig Gentry; Zulfikar Ramzan; Stuart G. Stubblebine

    2005-01-01

    This paper is a preliminary exploration of secure distributed computation. We consider the general paradigm of using large-scale distributed computation to solve difficult problems, but where humans can act as agents and provide candidate solutions. We are especially motivated by problem classes that appear to be difficult for computers to solve effectively, but are easier for humans; e.g., image analysis,

  8. Environment and the Humanities.

    ERIC Educational Resources Information Center

    Allen, Rodney F., Ed.; And Others

    As a conference report, the booklet is primarily devoted to abstracts of papers presented at a Conference on Environment and Humanities held in Tallahassee, Florida, April 25-27, 1976. Dr. Huston Smith of Syracuse University, the main speaker, addressed the issue of "Humanities and Environmental Awareness." Other topics discussed included: (1)…

  9. HUMAN CARCINOGENESIS BY ARSENIC

    EPA Science Inventory

    Arsenic is one of the few human carcinogens for which there is not yet a reliable animal cancer model. s such, the classification of arsenic as a carcinogen is based upon data derived from human epidemiologic studies. Although the mechanisms of action of arsenic as a toxic agent ...

  10. Human Performance Improvement

    E-print Network

    Human Performance Improvement When elite athletes become fatigued, their competitive edge may be lost. In emergency services and Defence scenarios, fatigue may be fatal, so monitoring human into the consumer sporting domain, where we plan to extend behaviour analysis to triathlon activity and gymnasium

  11. Quantifying Human Performance Reliability.

    ERIC Educational Resources Information Center

    Askren, William B.; Regulinski, Thaddeus L.

    Human performance reliability for tasks in the time-space continuous domain is defined and a general mathematical model presented. The human performance measurement terms time-to-error and time-to-error-correction are defined. The model and measurement terms are tested using laboratory vigilance and manual control tasks. Error and error-correction…

  12. Introduction to human factors

    SciTech Connect

    Winters, J.M.

    1988-03-01

    Some background is given on the field of human factors. The nature of problems with current human/computer interfaces is discussed, some costs are identified, ideal attributes of graceful system interfaces are outlined, and some reasons are indicated why it's not easy to fix the problems. (LEW)

  13. integration division Human Systems

    E-print Network

    integration division Human Systems Eye-Movement Metrics: Non-Intrusive Quantitative Tools for Monitoring Human Visual Performance Objective Approach Impact A reliable quantitative yet non to the engineer, which is critical for the reasoned identification and resolution of design trade-offs. Eye

  14. Dogs catch human yawns.

    PubMed

    Joly-Mascheroni, Ramiro M; Senju, Atsushi; Shepherd, Alex J

    2008-10-23

    This study is the first to demonstrate that human yawns are possibly contagious to domestic dogs (Canis familiaris). Twenty-nine dogs observed a human yawning or making control mouth movements. Twenty-one dogs yawned when they observed a human yawning, but control mouth movements did not elicit yawning from any of them. The presence of contagious yawning in dogs suggests that this phenomenon is not specific to primate species and may indicate that dogs possess the capacity for a rudimentary form of empathy. Since yawning is known to modulate the levels of arousal, yawn contagion may help coordinate dog-human interaction and communication. Understanding the mechanism as well as the function of contagious yawning between humans and dogs requires more detailed investigation. PMID:18682357

  15. [AIDS and human rights].

    PubMed

    Rico, B; Uribe-Zúñiga, P; Panebianco-Labbé, S; del Río-Chiriboga, C

    1995-01-01

    AIDS and human rights are closely related issues. This paper describes the relationship between AIDS and human rights, the impact and consequences of discrimination and the importance of the defense of human rights as a cornerstone strategy in AIDS prevention. Some general ethical aspects are addressed and two dilemmas which have been raised by the epidemic are discussed: the apparent conflict between individual and community rights and the reactions of intolerance and repression from those who claim that only through coercive strategies will the epidemic be brought under control. Specific problems in Mexico are described based on data collected at CONASIDA's Human Rights Department between 1992 and 1994. Finally some conclusions are stated emphasizing that, in the AIDS epidemic, the defense of human rights is the cornerstone of any public health strategy. PMID:8599140

  16. Beliefs about Human Extinction

    SciTech Connect

    Tonn, Bruce Edward [ORNL

    2009-11-01

    This paper presents the results of a web-based survey about futures issues. Among many questions, respondents were asked whether they believe humans will become extinct. Forty-five percent of the almost 600 respondents believe that humans will become extinct. Many of those holding this believe felt that humans could become extinct within 500-1000 years. Others estimated extinction 5000 or more years into the future. A logistic regression model was estimated to explore the bases for this belief. It was found that people who describe themselves a secular are more likely to hold this belief than people who describe themselves as being Protestant. Older respondents and those who believe that humans have little control over their future also hold this belief. In addition, people who are more apt to think about the future and are better able to imagine potential futures tend to also believe that humans will become extinct.

  17. Archaea on Human Skin

    PubMed Central

    Probst, Alexander J.; Auerbach, Anna K.; Moissl-Eichinger, Christine

    2013-01-01

    The recent era of exploring the human microbiome has provided valuable information on microbial inhabitants, beneficials and pathogens. Screening efforts based on DNA sequencing identified thousands of bacterial lineages associated with human skin but provided only incomplete and crude information on Archaea. Here, we report for the first time the quantification and visualization of Archaea from human skin. Based on 16 S rRNA gene copies Archaea comprised up to 4.2% of the prokaryotic skin microbiome. Most of the gene signatures analyzed belonged to the Thaumarchaeota, a group of Archaea we also found in hospitals and clean room facilities. The metabolic potential for ammonia oxidation of the skin-associated Archaea was supported by the successful detection of thaumarchaeal amoA genes in human skin samples. However, the activity and possible interaction with human epithelial cells of these associated Archaea remains an open question. Nevertheless, in this study we provide evidence that Archaea are part of the human skin microbiome and discuss their potential for ammonia turnover on human skin. PMID:23776475

  18. [On bedside medical humanities].

    PubMed

    Barilan, M; Sharon, D

    2001-12-01

    This article presents a challenge which we call "the humane gap in medicine" and also raises some ideas on how to meet this challenge. This is the gap between the capacities of biomedicine as a bureaucratic and scientific establishment and the medical needs and expectations of its beneficiaries. It is argued that successful medicine relies on two pillars. The first is the corpus of biomedical knowledge, while the other is knowing the patients within their bio-psycho-social life-world. Both the second pillar and the bridging of the two pillars are dependent on the Humanities. The humanities in medicine also provide healthcare professionals with means of support against devastating encounters with suffering, disability or the relentless pressures of academic careers and overwhelming physical labor. The humanities serve as a shared platform for all healthcare providers, diminishing traditional, and sometimes obstructive, boundaries such as those that may exist between doctors and nurses. We provide a list of possible benefits that the Humanities may bring to clinical practice and medical education. We conclude with some suggestions on how the humanities may be incorporated into medical education and implemented at the bedside. We suggest that art students attend anatomical labs; courses in medical humanities be opened for the benefit of all students, within the faculty of medicine and beyond. We encourage students from every faculty to undertake academic activities which will combine voluntary work with the sick with participatory observation in the tradition of cultural anthropology. PMID:11789308

  19. HUMAN SUBJECT PAYMENTS Policy Statement

    E-print Network

    Shahriar, Selim

    Page 1 HUMAN SUBJECT PAYMENTS Policy Statement This policy outlines the requirements for Northwestern University to comply with requirements of the Human Subject Protection Program (HSPP), University Human Resource policies and practices, the Internal Revenue Service (IRS), and University purchasing

  20. UNDERGRADUATE STUDENT MANUAL HUMAN PHYSIOLOGY

    E-print Network

    Guenther, Frank

    UNDERGRADUATE STUDENT MANUAL FOR HUMAN PHYSIOLOGY 2012-2013 Revised: September, 2012 (JLS) #12;- 2 ................................................................................................................. - 3 - II. INTRODUCTION TO THE DEPARTMENT OF HEALTH SCIENCES PROGRAM IN HUMAN PHYSIOLOGY........................................................................................................................................ - 4 - III. FULL-TIME FACULTY IN HUMAN PHYSIOLOGY

  1. UNDERGRADUATE STUDENT MANUAL HUMAN PHYSIOLOGY

    E-print Network

    Guenther, Frank

    UNDERGRADUATE STUDENT MANUAL FOR HUMAN PHYSIOLOGY 2011-2012 Revised: September, 2011 (JLS) #12;- 2 ................................................................................................................. - 3 - II. INTRODUCTION TO THE DEPARTMENT OF HEALTH SCIENCES PROGRAM IN HUMAN PHYSIOLOGY........................................................................................................................................ - 4 - III. FULL-TIME FACULTY IN HUMAN PHYSIOLOGY

  2. HUMAN SERVICES Mental Health Services

    E-print Network

    Escher, Christine

    procedures. Federal government, Departments of Health and Human Services Justice Veterans AdministrationPSYCHOLOGY HUMAN SERVICES Counseling Advocacy Mental Health Services STRATEGIESAREAS EMPLOYERS State government, Departments of Human Services Mental Health & Mental Retardation Community mental

  3. Human Resources Simon Fraser University

    E-print Network

    Kavanagh, Karen L.

    Human Resources Simon Fraser University Administrative and Professional Staff Job Description A. Identification Position Number: 31482 Position Title: Administrative Assistant (Human Resources Liaison) Name guidance, direction, coordination and effective management and implementation of SFU's Human Resources

  4. Director Human Resources Assoc Director

    E-print Network

    Botea, Adi

    Director ­ Human Resources Assoc Director Workforce Planning & Organisational Change Director ­ Human Resources Employment Services Support staff - EA/Receptionist - Snr Admin (Finance project leaders Human Resources Division Structure ­ as at 29 January 2013 * These teams are a reporting

  5. Associate Vice President Human Resources

    E-print Network

    Arnold, Jonathan

    Associate Vice President Human Resources Enjoy Athens! Great schools Affordable housing Eclectic Vice President for Human Resources. This position reports directly to the Vice President for Finance and Administration and provides leadership for the University's human resources programs and services

  6. HUMAN RESOURCES SIMON FRASER UNIVERSITY

    E-print Network

    HUMAN RESOURCES SIMON FRASER UNIVERSITY ADMINISTRATIVE AND PROFESSIONAL STAFF POSITION DESCRIPTION the management of departmental resources including: financial, human resources, facilities, and administrative or Associate Dean, and liaises with University administrators, other universities, finance, and human resources

  7. M. Phil. in Digital Humanities

    E-print Network

    O'Mahony, Donal E.

    M. Phil. in Digital Humanities and Culture Why choose this course?Internship Entry Requirements Associate Professor in Digital Humanities, Trinity College Dublin, Dublin 2, Ireland. Telephone: 00353 experience working with cultural heritage partners or digital humanities projects. The internship

  8. Empathy and humanity.

    PubMed

    Fuchsman, Ken

    2015-01-01

    This has been called the Age of Empathy; empathy is seen as the glue that holds society together, the capacity without which humans would not have evolved. It is the ability to accurately perceive others internal states and to have affective responses to them. Empathy is most likely to emerge with those with whom we are familiar, those that are an 'us'. Universally, humans divide 'us' and 'them.' Those in the out-group are treated with disdain, and sometimes with lethal actions. In human history and psychology, trends often move in opposite directions. Empathy has a limited domain, and is accompanied by hostility to 'outsiders'. PMID:25630194

  9. Human Rights in China

    NSDL National Science Digital Library

    Created in 1989, Human Rights in China is one of the major sources of information on human rights conditions in the People's Republic of China. The site offers press releases, reports, articles from its quarterly journal, China Rights Forum, organizational work reports, educational materials, action ideas and related links. In addition, the site covers a number of topics, including political prisoners and dissent, legal reform, freedom of association, women's rights, workers' rights, children's rights, and human rights education. The entire site is also available in Chinese.

  10. Human Genome Project

    SciTech Connect

    Block, S.; Cornwall, J.; Dally, W.; Dyson, F.; Fortson, N.; Joyce, G.; Kimble, H. J.; Lewis, N.; Max, C.; Prince, T.; Schwitters, R.; Weinberger, P.; Woodin, W. H.

    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.

  11. Human dignity, humiliation, and torture.

    PubMed

    Luban, David

    2009-09-01

    Modern human rights instruments ground human rights in the concept of human dignity, without providing an underlying theory of human dignity. This paper examines the central importance of human dignity, understood as not humiliating people, in traditional Jewish ethics. It employs this conception of human dignity to examine and criticize U.S. use of humiliation tactics and torture in the interrogation of terrorism suspects. PMID:19886522

  12. Finland and the Humanities.

    ERIC Educational Resources Information Center

    Fromm, Hans

    1986-01-01

    Reviews the status of the humanities in Finland, beginning with the post World War II era. Comments on state-supported programs and the successes achieved in such areas as linguistics, philology, literature, and historical research. (JDH)

  13. Human Genome Center

    NSDL National Science Digital Library

    Human Genome Center At Lawrence Berkeley Lab (LBL), Berkeley, California: offering information about projects in Biology, Informatics and Instrumentation, photos of LBL robotic instruments, software, and online access to one LBL genomic database.

  14. Algorithms for Human Genetics

    E-print Network

    KIRKPATRICK, BONNIE

    2011-01-01

    and Marianne Peters. Human sperm competition: testis size,sperm typing and linkage disequilibrium analyses reveals differences in selective pressures or recombination rates across humanhuman females [ 20]. On the other hand, male recombination rates can be inexpensively estimated from sperm-

  15. Aerospace Human Factors

    NASA Technical Reports Server (NTRS)

    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.

  16. Human Resources & Rebecca Leinen

    E-print Network

    Acton, Scott

    Development And Integration Systems Control Center Instrumentation and Metering Geospatial Engineering. Rainey Landscape Facilities Maintenance HVAC, Fire Systems, Elevators Maintenance Services CentralHuman Resources & Training Rebecca Leinen SafetyInformation Systems Chris Smeds Work Management

  17. Human X chromosome

    SciTech Connect

    NONE

    1993-12-31

    Chapter 21, describes in detail the human X chromosome. X chromatin (or Barr body) formation, inactivation and reactivation of the X chromosome, X;Y translocations, and sex reversal are discussed. 30 refs., 3 figs.

  18. HUMAN RESOURCES Purdue University

    E-print Network

    Fernández-Juricic, Esteban

    HUMAN RESOURCES Programs Purdue University Health Plan Coverage Overthecounter items: · Nicotine gum · Nicotine lozenge · Nicotine transdermal patch Prescriptions: · Chantix tabs, dose packs · Nicotine nasal spray · Nicotine inhalation · Bupropion 150mg SR/ Zyban 150mg To get these products, take

  19. Approaches to Human Communication.

    ERIC Educational Resources Information Center

    Budd, Richard W., Ed.; Ruben, Brent D., Ed.

    This anthology of essays approaches human communication from the points of view of: anthropology, art biology, economics, encounter groups, semantics, general system theory, history, information theory, international behavior, journalism, linguistics, mass media, neurophysiology, nonverbal behavior, organizational behavior, philosophy, political…

  20. Human Computers 1947

    NASA Technical Reports Server (NTRS)

    1947-01-01

    Langley's human computers at work in 1947. The female presence at Langley, who performed mathematical computations for male staff. Photograph published in Winds of Change, 75th Anniversary NASA publication (page 48), by James Schultz.

  1. Teleoperator human factors study

    NASA Technical Reports Server (NTRS)

    1984-01-01

    The progress made on the Teleoperator Human Factors Study program is summarized. Technical and programmatic problems that were encountered were discussed along with planned activities. The report contains four sections: Work Performed, Future Work, Problems Encountered, and Cost Information

  2. Teleoperator human factors study

    NASA Technical Reports Server (NTRS)

    1984-01-01

    The progress made on the Teleoperator Human Factors Study program is summarized. Technical and programmatic problems that were encountered are discussed along with planned activity. Work performed, future work, problems encountered, and cost information comprise the topics addressed herein.

  3. Human Reliability Program Overview

    SciTech Connect

    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.

  4. What makes us human?

    E-print Network

    Mikkelsen, Tarjei S.

    The sequence of chimpanzee chromosome 22 is starting to help us to define the set of genetic attributes that are unique to humans, but interpreting the biological consequences of these remains a major challenge.

  5. Backyard Burning: Human Health

    MedlinePLUS

    ... lasting substances that can build up in the food chain to levels that are harmful to human and ... concentration levels increase as they move up the food chain. As a consequence, animals at the top of ...

  6. Pushing Human Frontiers

    NASA Technical Reports Server (NTRS)

    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.

  7. [The human vomeronasal organ].

    PubMed

    Knecht, M; Witt, M; Abolmaali, N; Hüttenbrink, K B; Hummel, T

    2003-10-01

    Odors influence human behavior. The perception of so-called pheromones is frequently mentioned in the context of a functional vomeronasal organ. Vomeronasal ducts can be detected in approximately half of the population. Its functionality, still a matter of debate, seems to be unlikely, at least after birth. It is easily conceivable that pheromone-induced changes in behavior are mediated through receptors in the human olfactory epithelium. PMID:14551689

  8. Engineering Human Cooperation

    Microsoft Academic Search

    Terence C. Burnham; Brian Hare

    2007-01-01

    In a laboratory experiment, we use a public goods game to examine the hypothesis that human subjects use an involuntary eye-detector\\u000a mechanism for evaluating the level of privacy. Half of our subjects are “watched” by images of a robot presented on their\\u000a computer screen. The robot—named Kismet and invented at MIT—is constructed from objects that are obviously not human with

  9. Computational Human Body Models

    Microsoft Academic Search

    Jac Wismans; Riender Happee; J. A. W. Dommelen

    Computational human body models are widely used for automotive crashsafety research and design and as such have significantly\\u000a contributed to a reduction of traffic injuries and fatalities. Currently crash simulations are mainly performed using models\\u000a based on crash-dummies. However crash dummies differ significantly from the real human body and moreover crash dummies are\\u000a only available for a limited set of

  10. Genetics of human hydrocephalus

    Microsoft Academic Search

    Jun Zhang; Michael A. Williams; Daniele Rigamonti

    2006-01-01

    Human hydrocephalus is a common medical condition that is characterized by abnormalities in the flow or resorption of cerebrospinal\\u000a fluid (CSF), resulting in ventricular dilatation. Human hydrocephalus can be classified into two clinical forms, congenital\\u000a and acquired. Hydrocephalus is one of the complex and multifactorial neurological disorders.\\u000a \\u000a A growing body of evidence indicates that genetic factors play a major role

  11. Cholesterol and Human Health

    Microsoft Academic Search

    Hongbao Ma

    2006-01-01

    Cholesterol plays a major role in human heart health and high cholesterol is a leading risk factor for human cardiovascular disease such as coronary heart disease and stroke. There are 102.3 million American adults who have total blood cholesterol values of 200 mg\\/dl and higher, and about 41.3 million. Cholesterol can be good (high-density lipoprotein) or bad (low-density lipoprotein) to

  12. Human neuronal nicotinic receptors

    Microsoft Academic Search

    C. Gotti; D. Fornasari; F. Clementi

    1997-01-01

    Nicotine is a very widely used drug of abuse, which exerts a number of neurovegetative, behavioural and psychological effects by interacting with neuronal nicotinic acetylcholine receptors (NAChRs). These receptors are distributed widely in human brain and ganglia, and form a family of ACh-gated ion channels of different subtypes, each of which has a specific pharmacology and physiology. As human NAChRs

  13. Human ocular anatomy.

    PubMed

    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. PMID:25704934

  14. Human Development Report 2005

    NSDL National Science Digital Library

    2005-01-01

    The notion of human development is one that is quite old, even if it has not always gone by that name. The United Nations understands human development to be about â??creating an environment in which people can develop their full potential and lead productive, creative lives in accord with their needs and interestsâ?. In this way, of course, many ancient city-states and other such communities of shared interests have always been about creating such an environment. This latest report on the state of human development affords curious individuals an insight into the United Nationsâ?? work in this area. It offers some insights into the nature of inequalities which affect the potentiality of human development schemes and also looks at other related processes such as the nature of international trade and violent conflict. The report is divided into five primary chapters, and is supplemented by a list of human development indicators and a bibliography. The site also contains an animated file that offers a visualization of the trend of human development.

  15. [Atypical human trypanosomoses].

    PubMed

    Truc, P; Nzoumbou-Boko, R; Desquesnes, M; Semballa, S; Vincendeau, P

    2014-01-01

    Trypanosomes are principally responsible for two human diseases: human African trypanosomiasis (HAT) or sleeping sickness (caused by Trypanosoma brucei gambiense and T. b. rhodesiense), and Chagas disease, also called South American trypanosomiasis (T. cruzi). However, some trypanosomes that are natural parasites only of animals can sometimes infect humans and cause the so-called "atypical human trypanosomiases" (aHT). T. evansi, the agent causing surra in camels, horses, dogs, and bovines, and T. lewisi, a cosmopolite rat parasite, are the most frequently involved. These atypical infections involve no or only minor symptoms, but major symptoms are sometimes present. Parasite elimination is generally spontaneous, but can require treatment. Molecular tools, such as polymerase chain reaction, have improved the accuracy of parasite identification. Immunological techniques, mainly immunoenzymatic assays, can detect asymptomatic subjects. Several causes, most often concomitant, have been hypothesized, including immune immaturity, immunodeficiency, and close contact with infected animals. Innate immunity to animal trypanosomes depends on a trypanolytic factor called apolipoprotein L-I, present in human serum. A deficit in both apolipoprotein L-I alleles has been reported in an Indian patient infected by T. evansi. The prevalence of aHT is probably underestimated. Moreover, these trypanosomes might become potential emerging zoonotic pathogens, due to their ability to invade new hosts. An international network has been set up to survey these aHT (NAHIAT: Network on Atypical Human Infections by Animal Trypanosomes). PMID:24918468

  16. Genomics of human longevity

    PubMed Central

    Slagboom, P. E.; Beekman, M.; Passtoors, W. M.; Deelen, J.; Vaarhorst, A. A. M.; Boer, J. M.; van den Akker, E. B.; van Heemst, D.; de Craen, A. J. M.; Maier, A. B.; Rozing, M.; Mooijaart, S. P.; Heijmans, B. T.; Westendorp, R. G. J.

    2011-01-01

    In animal models, single-gene mutations in genes involved in insulin/IGF and target of rapamycin signalling pathways extend lifespan to a considerable extent. The genetic, genomic and epigenetic influences on human longevity are expected to be much more complex. Strikingly however, beneficial metabolic and cellular features of long-lived families resemble those in animals for whom the lifespan is extended by applying genetic manipulation and, especially, dietary restriction. Candidate gene studies in humans support the notion that human orthologues from longevity genes identified in lower species do contribute to longevity but that the influence of the genetic variants involved is small. Here we discuss how an integration of novel study designs, labour-intensive biobanking, deep phenotyping and genomic research may provide insights into the mechanisms that drive human longevity and healthy ageing, beyond the associations usually provided by molecular and genetic epidemiology. Although prospective studies of humans from the cradle to the grave have never been performed, it is feasible to extract life histories from different cohorts jointly covering the molecular changes that occur with age from early development all the way up to the age at death. By the integration of research in different study cohorts, and with research in animal models, biological research into human longevity is thus making considerable progress. PMID:21115528

  17. Genomics of human longevity.

    PubMed

    Slagboom, P E; Beekman, M; Passtoors, W M; Deelen, J; Vaarhorst, A A M; Boer, J M; van den Akker, E B; van Heemst, D; de Craen, A J M; Maier, A B; Rozing, M; Mooijaart, S P; Heijmans, B T; Westendorp, R G J

    2011-01-12

    In animal models, single-gene mutations in genes involved in insulin/IGF and target of rapamycin signalling pathways extend lifespan to a considerable extent. The genetic, genomic and epigenetic influences on human longevity are expected to be much more complex. Strikingly however, beneficial metabolic and cellular features of long-lived families resemble those in animals for whom the lifespan is extended by applying genetic manipulation and, especially, dietary restriction. Candidate gene studies in humans support the notion that human orthologues from longevity genes identified in lower species do contribute to longevity but that the influence of the genetic variants involved is small. Here we discuss how an integration of novel study designs, labour-intensive biobanking, deep phenotyping and genomic research may provide insights into the mechanisms that drive human longevity and healthy ageing, beyond the associations usually provided by molecular and genetic epidemiology. Although prospective studies of humans from the cradle to the grave have never been performed, it is feasible to extract life histories from different cohorts jointly covering the molecular changes that occur with age from early development all the way up to the age at death. By the integration of research in different study cohorts, and with research in animal models, biological research into human longevity is thus making considerable progress. PMID:21115528

  18. Infants' Responses to Real Humans and Representations of Humans

    ERIC Educational Resources Information Center

    Heron, Michelle; Slaughter, Virginia

    2010-01-01

    Infants' responses to typical and scrambled human body shapes were assessed in relation to the realism of the human body stimuli presented. In four separate experiments, infants were familiarized to typical human bodies and then shown a series of scrambled human bodies on the test. Looking behaviour was assessed in response to a range of different…

  19. Humans in the Loop: Human-Computer Interaction and Security

    Microsoft Academic Search

    Sean W. Smith

    2003-01-01

    The security field suffers from an endemic problem: despite our best efforts, the current infrastructure is continually full of security vulnerabilities. The systems that comprise this infrastructure also are full of boundaries and interfaces where humans and systems must interact: most secure systems exist to serve human users and carry out human-oriented processes, and are designed and built by humans.

  20. Human genome diversity: What about the other human genome project?

    Microsoft Academic Search

    Henry T. Greely

    2001-01-01

    Although the Human Genome Project has been successful, the Human Genome Diversity Project, proposed in 1991, has so far failed to thrive. One of the main values in studying the human genome, however, will come from examining its variations and their effects. To do that in a systematic way, an active Human Genome Diversity Project, or something very similar, will

  1. Policy on Human Subjects Research Policy on Human Subjects

    E-print Network

    Sridhar, Srinivas

    Policy on Human Subjects Research 10/15/2014 Policy on Human Subjects Research I. Purpose and Scope ethical standards for the protection of human subjects, consistent with the principles of the Nuremberg Code and the Belmont Report. Accordingly, the University has established the Office of Human Subject

  2. 237Poverty and Human Capability Studies Poverty and Human

    E-print Network

    Dresden, Gregory

    237Poverty and Human Capability Studies Poverty and Human CaPability StudieS (Pov) Core Fa and Human Capability offers a cur- ricular and cocurricular program of study that enriches any major to establish a decent minimum of human development for all people. Students complet- ing designated

  3. HUMAN RESOURCE USE ONLY HUMAN RESOURCE REVIEW: DATE

    E-print Network

    HUMAN RESOURCE USE ONLY HUMAN RESOURCE REVIEW: DATE: IMAGENOW SCAN/LINK DATE INDEXING: COMP & CLASS please send an email to benefitsinfo@hr.msu.edu or call Human Resources at 3-4434. *For Academic Units is for the Dean's office. SEND TO HUMAN RESOURCES (HR), 110 NISBET #12;

  4. The Human Genome From human genome to other

    E-print Network

    Linial, Michal

    The Human Genome Project From human genome to other genomes and to gene function June 2000 From genome to health Structural Genomics initiative #12;What is the Human Genome Project? · U.S. govt that arise from genome research #12;The Human Genome Project Project began in 1990 as a $3 billion, 15-year

  5. High Orotate Phosphoribosyltransferase Gene Expression Predicts Complete Response to Chemoradiotherapy in Patients with Squamous Cell Carcinoma of the Esophagus

    Microsoft Academic Search

    Takeshi Kajiwara; Tomohiro Nishina; Ichinosuke Hyodo; Toshikazu Moriwaki; Shinji Endo; Junichirou Nasu; Shinichiro Hori; Bunzo Matsuura; Yoichi Hiasa; Morikazu Onji

    2009-01-01

    Objective: Chemoradiotherapy (CRT) is a possible alternative to surgery for esophageal cancer. As complete response (CR) to CRT is essential for a good prognosis, potential biomarkers predictive of CR were explored. Methods: Endoscopic tumor biopsies were obtained from 41 patients with stage II–III esophageal squamous cell carcinoma before 5-fluorouracil\\/cisplatin-based definitive CRT. cDNA was derived from RNA isolated from microdissected tumor

  6. The Three-Dimensional Structures of Nicotinate Mononucleotide:5,6-Dimethylbenzimidazole Phosphoribosyltransferase (CobT) from

    E-print Network

    Rayment, Ivan

    The Three-Dimensional Structures of Nicotinate Mononucleotide:5,6-Dimethylbenzimidazole, Wisconsin ReceiVed July 28, 1999; ReVised Manuscript ReceiVed September 23, 1999 ABSTRACT: Nicotinate,6-dimethylbenzimidazole, and second, a complex of CobT with its reaction products, nicotinate and R-ribazole-5-phosphate

  7. Developing Human Performance Measures

    SciTech Connect

    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 framework, 3) how our use of modeling and simulation techniques could be used to develop and validate measures of human performance, and 4) what the possible outcomes are from this research as the modeling and simulation efforts generate results.

  8. Human Modeling For Ground Processing Human Factors Engineering Analysis

    NASA Technical Reports Server (NTRS)

    Tran, Donald; Stambolian, Damon; Henderson, Gena; Barth, Tim

    2011-01-01

    There have been many advancements and accomplishments over that last few years using human modeling for human factors engineering analysis for design of spacecraft and launch vehicles. The key methods used for this are motion capture and computer generated human models. The focus of this paper is to explain the different types of human modeling used currently and in the past at Kennedy Space Center (KSC) currently, and to explain the future plans for human modeling for future spacecraft designs.

  9. Meeting human needs

    NASA Technical Reports Server (NTRS)

    Nicogossian, Arnauld E.

    1992-01-01

    Manned space flight can be viewed as an interaction of three general elements: the human crewmember, spacecraft systems, and the environment. While the human crewmember is a crucial element in the system, certain physiological, psychological, environ- mental and spacecraft systems factors can compromise human performance in space. These factors include atmospheric pressure, physiology, uncertainties associated with space radiation, the potential for exposure to toxic materials in the closed environment, and spacecraft habitability. Health protection in space, for current and future missions, relies on a philosophy of risk reduction, which in the space program is achieved in four ways-through health maintenance, health care, design criteria, an selection and training. Emphasis is place upon prevention, through selection criteria and careful screening. Spacecraft health care systems must be absolutely reliable, and they will be automated and computerized to the maximum extent possible, but still designed with the human crewmember's capabilities in mind. The autonomy and technological sophistication of future missions will require a greater emphasis on high-level interaction between the human operator and automated systems, with effective allocation of tasks between humans and machines. Performance in space will include complex tasks during extravehicular activity (EVA) and on planetary surfaces, and knowledge of crewmembers' capability and limitations during such operations will be critical to mission success. Psychological support will become increasingly important on space missions, as crews spend long periods in remote and potentially hazardous environments. The success of future missions will depend on both individual psychological health and group cohesion and productivity, particularly as crew profiles become more heterogeneous. Thus, further human factors are needed in the area of small-group dynamics and performance.

  10. THE MIDAS HUMAN PERFORMANCE MODEL

    Microsoft Academic Search

    Sherman W. Tyler; Christian Neukom; Michael Logan; Jay Shively

    A unique software tool for conducting human factors analyses of complex human-machine systems has been developed at NASA Ames Research Center. Called the Man-Machine Integration Design and Analysis System (MIDAS), this simulation system contains models of human performance that can be used to evaluate candidate procedures, controls, and displays prior to more expensive and time consuming hardware simulators and human

  11. Time, Humans and Societal Challenges

    E-print Network

    to human and ecosystem health · Limited and not substitutable · Unevenly distributed · Movable? Human Well-being and Energy Use Human Development Index, measure of human well-being (health, education, living standard), reaches plateau at ~3 tons oil equivalent (toe) per capita (=pre-recession Italy, Spain

  12. Human Computation with Global Constraints

    E-print Network

    Bustamante, Fabián E.

    Chapter 3 Human Computation with Global Constraints Within studies of human computation be independently assigned to individuals in the crowd. This raises a significant challenge for human computation algorithms, as such 59 #12;Chapter 3: Human Computation with Global Constraints 60 Figure 3.1: Planning

  13. Human Centric Computing School COMSC

    E-print Network

    Martin, Ralph R.

    Human Centric Computing School COMSC As information systems become more pervasive and complex. This module takes a systems approach to Human Centric Computing and deals with relevant aspects of Human and Pervasive Computing. #12;· Characterise and analyse systems and understand why humans make errors. · Assess

  14. Human bites - self-care

    MedlinePLUS

    A human bite can break, puncture, or tear the skin. Human bites that break the skin can be very ... Bites - human - self-care ... Human bites can occur in two ways: If someone bites you If your hand comes into contact ...

  15. Humanities Division UNIVERSITY OF OXFORD

    E-print Network

    Oxford, University of

    Humanities Division UNIVERSITY OF OXFORD HUMANITIES DIVISION MELLON POSTDOCTORAL FELLOWSHIP SCHEME A two-year research and teaching appointment in Digital Humanities from October 2011 for an outstanding Postdoctoral Fellow in Digital Humanities will: · take up appointment between 1 October 2011 and 1 January 2012

  16. Humanities Division Janel Mueller, Dean

    E-print Network

    He, Chuan

    Humanities Division Janel Mueller, Dean Thomas Thuerer, Dean of Students Larry Norman, Associate Dean Division of the Humanities 1010 East 59th Street University of Chicago Chicago, IL 60637 Tel: (773) 702-8512 Fax: (773) 702-9861 http://humanities.uchicago.edu Apply to Humanities Programs online

  17. Human Challenges in Exploration Missions

    NASA Technical Reports Server (NTRS)

    Lloyd, Charles W.

    2007-01-01

    This viewgraph presents an overview using pictures some of the history of human exploration of the new frontiers of Earth and then examines some of the challenges to human exploration of space. Particular attention is given to the environmental factors and to the social and human factors that effect humans in space environments.

  18. Introduction Pondering on Digital Humanities

    E-print Network

    Chu, Hao-hua

    1* 2** * ** #12;010 Introduction Pondering on Digital Humanities: Foundation and Methodology Jieh Hsiang3*, Chi-an Weng4** Abstract As Digital Humanities gains popularity and extends its reach into more domains of humanities, it becomes imperative to consider issues facing Digital Humanities as it emerges

  19. Resources and Human Impact

    NSDL National Science Digital Library

    National Science Teachers Association (NSTA)

    2008-09-30

    Overview: The Resources and Human Impact SciPack explores the role society plays in environmental degradation, and the technological solutions, including resource management, that arises from environmental issues. Human beings modify all components of Earth's ecosystems as they use and consume available resources. The amount and rate of consumption is affected by the population growth and access to technology. This SciPack is focused on Standards and Benchmarks related to interactions in and between ecosystem; population growth and carrying capacity; resource use; and environmental degradation and changes to Earth's systems.In addition to comprehensive inquiry-based learning materials tied to Science Education Standards and Benchmarks, the SciPack includes the following additional components: Pedagogical Implications section addressing common misconceptions, teaching resources and strand maps linking grade band appropriate content to standards. Access to one-on-one support via e-mail to content "Wizards". Final Assessment which can be used to certify mastery of the concepts. Learning Outcomes: Resources and Human Impact: Earth as a System Identify examples of biotic and abiotic interactions within a system. Define carrying capacity. Identify how biotic and abiotic factors limit the carrying capacity of a system. Identify how elements of the environment influence carrying capacity (energy, water, food, minerals). Identify the resources that the human population needs for survival (air, water, food, etc.) Identify which scenario (when given several) is NOT an example of a systematic interaction (feedback loop). Resources and Human Impact: Population Growth, Technology, and the Environment Identify, compare, and contrast principles of population growth in humans and other organisms. Explain the limiting factors on the exponential growth of a population (for example: disease, competition for resources). Analyze how technology (antibiotics, harvesting food) has impacted human population growth in an ecosystem (for example: agriculture, aquaculture). Resources and Human Impact: Environmental Degradation Compare and contrast ways in which different technologies have impacted the environmental system. Differentiate between examples of renewable resources and non-renewable (finite) resources. Analyze how the extraction of each type of energy negatively impacts the environment. Summarize how the burning of fossil fuels is affecting the environment. Assess both local and global environmental impacts when given examples of human resource use. Identify ways in which one human-based environmental change can have a domino-effect on the rest of the ecosystem (when given a scenario). Resources and Human Impact: Using Technology to Address Resource Use Issues Identify the social, political, and economic factors that have affected the development and implementation of technological advances. Identify a technological solution to manage the human impact(s) of a given problem, such as surface mining on the ecosystem. Identify potential risks of implementing a technological solution to manage the human impact(s) upon the ecosystem (for example: unintended outcomes).

  20. The Human Serum Metabolome

    PubMed Central

    Psychogios, Nikolaos; Hau, David D.; Peng, Jun; Guo, An Chi; Mandal, Rupasri; Bouatra, Souhaila; Sinelnikov, Igor; Krishnamurthy, Ramanarayan; Eisner, Roman; Gautam, Bijaya; Young, Nelson; Xia, Jianguo; Knox, Craig; Dong, Edison; Huang, Paul; Hollander, Zsuzsanna; Pedersen, Theresa L.; Smith, Steven R.; Bamforth, Fiona; Greiner, Russ; McManus, Bruce; Newman, John W.; Goodfriend, Theodore; Wishart, David S.

    2011-01-01

    Continuing improvements in analytical technology along with an increased interest in performing comprehensive, quantitative metabolic profiling, is leading to increased interest pressures within the metabolomics community to develop centralized metabolite reference resources for certain clinically important biofluids, such as cerebrospinal fluid, urine and blood. As part of an ongoing effort to systematically characterize the human metabolome through the Human Metabolome Project, we have undertaken the task of characterizing the human serum metabolome. In doing so, we have combined targeted and non-targeted NMR, GC-MS and LC-MS methods with computer-aided literature mining to identify and quantify a comprehensive, if not absolutely complete, set of metabolites commonly detected and quantified (with today's technology) in the human serum metabolome. Our use of multiple metabolomics platforms and technologies allowed us to substantially enhance the level of metabolome coverage while critically assessing the relative strengths and weaknesses of these platforms or technologies. Tables containing the complete set of 4229 confirmed and highly probable human serum compounds, their concentrations, related literature references and links to their known disease associations are freely available at http://www.serummetabolome.ca. PMID:21359215

  1. Human herpesvirus 6.

    PubMed Central

    Braun, D K; Dominguez, G; Pellett, P E

    1997-01-01

    Human herpesvirus 6 variant A (HHV-6A) and human herpesvirus 6 variant B (HHV-6B) are two closely related yet distinct viruses. These visuses belong to the Roseolovirus genus of the betaherpesvirus subfamily; they are most closely related to human herpesvirus 7 and then to human cytomegalovirus. Over 95% of people older than 2 years of age are seropositive for either or both HHV-6 variants, and current serologic methods are incapable of discriminating infection with one variant from infection with the other. HHV-6A has not been etiologically linked to any human disease, but such an association will probably be found soon. HHV-6B is the etiologic agent of the common childhood illness exanthem subitum (roseola infantum or sixth disease) and related febrile illnesses. These viruses are frequently active and associated with illness in immunocompromised patients and may play a role in the etiology of Hodgkin's disease and other malignancies. HHV-6 is a commensal inhabitant of brains; various neurologic manifestations, including convulsions and encephalitis, can occur during primary HHV-6 infection or in immunocompromised patients. HHV-6 and distribution in the central nervous system are altered in patients with multiple sclerosis; the significance of this is under investigation. PMID:9227865

  2. Regulation of NAMPT in Human Gingival Fibroblasts and Biopsies

    PubMed Central

    Damanaki, Anna; Nokhbehsaim, Marjan; Götz, Werner; Winter, Jochen; Wahl, Gerhard; Jäger, Andreas; Jepsen, Søren

    2014-01-01

    Adipokines, such as nicotinamide phosphoribosyltransferase (NAMPT), are molecules, which are produced in adipose tissue. Recent studies suggest that NAMPT might also be produced in the tooth-supporting tissues, that is, periodontium, which also includes the gingiva. The aim of this study was to examine if and under what conditions NAMPT is produced in gingival fibroblasts and biopsies from healthy and inflamed gingiva. Gingival fibroblasts produced constitutively NAMPT, and this synthesis was significantly increased by interleukin-1? and the oral bacteria P. gingivalis and F. nucleatum. Inhibition of the MEK1/2 and NF?B pathways abrogated the stimulatory effects of F. nucleatum on NAMPT. Furthermore, the expression and protein levels of NAMPT were significantly enhanced in gingival biopsies from patients with periodontitis, a chronic inflammatory infectious disease of the periodontium, as compared to gingiva from periodontally healthy individuals. In summary, the present study provides original evidence that gingival fibroblasts produce NAMPT and that this synthesis is increased under inflammatory and infectious conditions. Local synthesis of NAMPT in the inflamed gingiva may contribute to the enhanced gingival and serum levels of NAMPT, as observed in periodontitis patients. Moreover, local production of NAMPT by gingival fibroblasts may represent a possible mechanism whereby periodontitis may impact on systemic diseases. PMID:24707118

  3. Journal of Digital Humanities

    NSDL National Science Digital Library

    The Journal of Digital Humanities is a comprehensive, peer-reviewed, open access journal that features "the best scholarship, tools, and conversations produced by the digital humanities community." This endeavor was started by the Press Forward Project and its rigorous evaluation process ensures that interested parties will be exposed to a wide range of talent and subject matter. Arranged by trimester, recent issues of the journal have focused in on the ways digital humanities projects can be used to teach undergraduates about the world around them, while also highlighting the pedagogy involved with such endeavors. Visitors can search through the entire collection of back issues or they may also look through the list of contributors to get a sense of those involved with the project.

  4. Human & Constitutional Rights

    NSDL National Science Digital Library

    The Arthur W. Diamond Law Library at Columbia Law School maintains this excellent resource for finding materials on human rights and constitutional rights. The metasite serves students, scholars, and practitioners as a portal to documents and Internet resources on international and domestic law related to human and constitutional rights. The information resources are divided into six sections: Country Reports, International Links, Regional Links, National Links, Documents, and Other Web Resources. Each section is clearly organized into neat lists or pop-up menus to ease navigation. Marylin Raisch -- the International, Comparative, and Foreign Law Librarian responsible for this metasite -- also provides a Hot Topics section, which posts information on current events related to human and constitutional rights.

  5. The human toxome project.

    PubMed

    Bouhifd, Mounir; Andersen, Melvin E; Baghdikian, Christina; Boekelheide, Kim; Crofton, Kevin M; Fornace, Albert J; Kleensang, Andre; Li, Henghong; Livi, Carolina; Maertens, Alexandra; McMullen, Patrick D; Rosenberg, Michael; Thomas, Russell; Vantangoli, Marguerite; Yager, James D; Zhao, Liang; Hartung, Thomas

    2015-01-01

    The Human Toxome Project, funded as an NIH Transformative Research grant 2011-2016, is focused on developing the concepts and the means for deducing, validating and sharing molecular pathways of toxicity (PoT). Using the test case of estrogenic endocrine disruption, the responses of MCF-7 human breast cancer cells are being phenotyped by transcriptomics and mass-spectroscopy-based metabolomics. The bioinformatics tools for PoT deduction represent a core deliverable. A number of challenges for quality and standardization of cell systems, omics technologies and bioinformatics are being addressed. In parallel, concepts for annotation, validation and sharing of PoT information, as well as their link to adverse outcomes, are being developed. A reasonably comprehensive public database of PoT, the Human Toxome Knowledge-base, could become a point of reference for toxicological research and regulatory test strategies. PMID:25742299

  6. Teleoperator Human Factors Study

    NASA Technical Reports Server (NTRS)

    1986-01-01

    An investigation of the spectrum of space teleoperation activities likely in the 1985 to 1995 decade focused on the resolution of critical human engineering issues and characterization of the technology effect on performance of remote human operators. The study began with the identification and documentation of a set of representative reference teleoperator tasks. For each task, technology, development, and design options, issues, and alternatives that bear on human operator performance were defined and categorized. A literature survey identified existing studies of man/machine issues. For each teleoperations category, an assessment was made of the state of knowledge on a scale from adequate to void. The tests, experiments, and analyses necessary to provide the missing elements of knowledge were then defined. A limited set of tests were actually performed, including operator selection, baseline task definition, control mode study, lighting study, camera study, and preliminary time delay study.

  7. Human Ageing Genomic Resources

    NSDL National Science Digital Library

    The Human Ageing Genomic Resources (HAGR)â??currently led by Dr. João Pedro de Magalhães at the Harvard Medical Schoolâ??is "a collection of databases and tools designed to help researchers understand the genetics of human ageing.â? Two major searchable resources offered in HAGR are AnAge, a curated animal ageing database with more than 2,000 species; and GenAge, â??a curated database of genes related to human ageing.â? Site visitors are encouraged to download the HAGR software, Ageing Resources Computational Tools, which â??is a toolkit of Perl modules based on the Bioperl package aimed a comparative genomics.â? Site users will also appreciate the solid list of related links organized into the following categories: Major Databases, Gerontology Databases, Computer Science, Comparative Biology, and Computational Biology.

  8. North Carolina Humanities Council

    NSDL National Science Digital Library

    Created in 1972, the North Carolina Humanities Council is a statewide nonprofit and affiliate of the National Endowment for the Humanities that works to make the humanities "a cornerstone of public life." The Council's bright and well-designed website contains information about grant-making initiatives, upcoming events and talks, and publications as well as a gallery of images. First-time visitors may want to start by browsing through the latest issues of "North Carolina Conversations," found under Publications. One recent issue included a profile of downtown Greensboro, a short story by John York, and information on traveling folklife exhibits. The Programs area contains vibrant information on the Council's "Road Scholars" initiative, which brings speakers to audiences around the state. Also, this area contains the "Museum on Main Street," which provides information on the traveling exhibit jointly sponsored by the Council and the Smithsonian Institution Traveling Exhibition. The Publications area contains the Council's annual reports and its newsletter, "Crossroads"

  9. Is humanity suicidal?

    PubMed

    Wilson, E O

    1993-01-01

    The world's fauna and flora has entered a crisis unparalleled since the end of the Mesozoic Era, with the extinction rate of species now elevated to more than a thousand times that existing before the coming of humanity. Scientists and policy makers are ill-prepared to moderate this hemorrhaging, because so little is known of the biology of the Earth's millions of species and because so little effort has been directed toward conservation thus far. With the vanished species will go great potential wealth in scientific knowledge, new products, ecosystems services, and part of the natural world in which the human species originated. The need for new research and improved management is thus urgent. If it is not met, humanity will likely survive, but in a world biologically impoverished for all time. PMID:8155855

  10. [Human rights and procreation].

    PubMed

    Leroy, F

    1990-04-01

    The impact of procreation on freedom, health and welfare of human beings, is considerable. This relationship, however, is not mirrored in texts devoted to Human Rights. This omission obviously implies a neglect of women's and children's rights. The history of anticonceptive methods exemplifies the struggle for these rights. This conquest, which has lasted two hundred years, is far from completed. Because of the demographic outbreak in Third World countries, an ideological conflict has appeared between first generation Human Rights concerned with individual freedom ("rights of") and those of second generation aiming at social fairness ("rights to"). Adequate political and economic adjustment between North and South is a prerequisite to any balanced compromise that would resolve this conflict through democratic, albeit intensive, birth control. PMID:2339216

  11. Avian and human metapneumovirus.

    PubMed

    Broor, Shobha; Bharaj, Preeti

    2007-04-01

    Pneumovirus infection remains a significant problem for both human and veterinary medicine. Both avian pneumovirus (aMPV, Turkey rhinotracheitis virus) and human metapneumovirus (hMPV) are pathogens of birds and humans, which are associated with respiratory tract infections. Based on their different genomic organization and low level of nucleotide (nt) and amino acid (aa) identity with paramyxoviruses in the genus Pneumovirus, aMPV and hMPV have been classified into a new genus referred to as Metapneumovirus. The advancement of our understanding of pneumovirus biology and pathogenesis of pneumovirus disease in specific natural hosts can provide us with strategies for vaccine formulations and combined antiviral and immunomodulatory therapies. PMID:17470912

  12. The Human Nature Review

    NSDL National Science Digital Library

    While attempting to cover one area of scholarly discipline in a Web site may be a formidable task, the editors of the Human Nature Review are concerned with any substantive scholarship or research dealing with human nature in its entirety. As the Web site notes: "Our goal is to bring into communication the variety of approaches to the understanding of human nature which have a regrettable tendency to be less in touch with one another than they might." The site is edited by Dr. Ian Pitchford of the Creighton University School of Medicine and Professor Robert M. Young. Prominent features of the site include an online dictionary of mental health, a daily review (sent as an email, if users so desire) of updates on ongoing scholarship in the fields of psychology and psychotherapy, and a number of complete online texts. Finally, the site also houses hundreds of book reviews, contributed by scholars from a diverse set of fields, on works of topical importance.

  13. Telocytes in human epicardium

    PubMed Central

    Popescu, L M; Manole, C G; Gherghiceanu, M; Ardelean, A; Nicolescu, M I; Hinescu, M E; Kostin, S

    2010-01-01

    Abstract The existence of the epicardial telocytes was previously documented by immunohistochemistry (IHC) or immunofluorescence. We have also demonstrated recently that telocytes are present in mice epicardium, within the cardiac stem-cell niches, and, possibly, they are acting as nurse cells for the cardiomyocyte progenitors. The rationale of this study was to show that telocytes do exist in human (sub)epicardium, too. Human autopsy hearts from 10 adults and 15 foetuses were used for conventional IHC for c-kit/CD117, CD34, vimentin, S-100, ?, Neurokinin 1, as well as using laser confocal microscopy. Tissue samples obtained by surgical biopsies from 10 adults were studied by digital transmission electron microscopy (TEM). Double immunolabelling for c-kit/CD34 and, for c-kit/vimentin suggests that in human beings, epicardial telocytes share similar immunophenotype features with myocardial telocytes. The presence of the telocytes in human epicardium is shown by TEM. Epicardial telocytes, like any of the telocytes are defined by telopodes, their cell prolongations, which are very long (several tens of ?m), very thin (0.1–0.2 ?m, below the resolving power of light microscopy) and with moniliform configuration. The interconnected epicardial telocytes create a 3D cellular network, connected with the 3D network of myocardial telocytes. TEM documented that telocytes release shed microvesicles or exocytotic multivesicular bodies in the intercellular space. The human epicardial telocytes have similar phenotype (TEM and IHC) with telocytes located among human working cardiomyocyte. It remains to be established the role(s) of telocytes in cardiac renewing/repair/regeneration processes, and also the pathological aspects induced by their ‘functional inhibition’, or by their variation in number. We consider telocytes as a real candidate for future developments of autologous cell-based therapy in heart diseases. PMID:20629996

  14. Sanitation and Human Health

    NSDL National Science Digital Library

    Science Netlinks

    2000-12-06

    The purpose of this Science NetLinks lesson is to develop an understanding of the impact of improved sanitation on human health. In this lesson, students learn something about the ways that sanitation technology has helped people by examining the history of sanitation in the context of disease outbreaks and comparing the quality of life in those times to that of today. By the end of this lesson, students should recognize that advances in health and human life expectancy have resulted in large part because of technologies that we now take for granted, such as modern waste-disposal, sanitary food handling, and refrigeration.

  15. Nature: The Human Genome

    NSDL National Science Digital Library

    This special Web Focus from the journal Nature presents research papers that "serve as the definitive historical record for the sequences and analyses of human chromosomes -- the ultimate results of the Human Genome Project." Papers are available for chromosomes 6, 7, 14, 20, 21, 22, and Y, which readers can access (no subscription required) by clicking on the image of the corresponding chromosome. The papers for chromosome 6 are the most recent, published in the October 23, 2003 issue of Nature. The website also offers free feature articles on the subject.

  16. Defining the Human Microbiome

    PubMed Central

    Ursell, Luke K; Metcalf, Jessica L; Parfrey, Laura Wegener; Knight, Rob

    2012-01-01

    Rapidly developing sequencing methods and analytical techniques are enhancing our ability to understand the human microbiome, and, indeed, how we define the microbiome and its constituents. In this review we highlight recent research that expands our ability to understand the human microbiome on different spatial and temporal scales, including daily timeseries datasets spanning months. Furthermore, we discuss emerging concepts related to defining operational taxonomic units, diversity indices, core versus transient microbiomes and the possibility of enterotypes. Additional advances in sequencing technology and in our understanding of the microbiome will provide exciting prospects for exploiting the microbiota for personalized medicine. PMID:22861806

  17. Memristance in human skin

    NASA Astrophysics Data System (ADS)

    Martinsen, Ø. G.; Grimnes, S.; Lütken, C. A.; Johnsen, G. K.

    2010-04-01

    The memristor is basically a resistor with memory, so that the resistance is dependent on the net amount of charge having passed through the device. It is the regarded the fourth fundamental component, in addition to the resistor, capacitor and inductor, that can be deduced from the four basic circuit variables; current, voltage, charge and magnetic flux. We show that memristors can be used for modelling electrical properties of human skin. In particular is electro-osmosis in human sweat ducts of memristive nature.

  18. Human push capability.

    PubMed

    Barnett, Ralph L; Liber, Theodore

    2006-02-22

    Use of unassisted human push capability arises from time to time in the areas of crowd and animal control, the security of locked doors, the integrity of railings, the removal of tree stumps and entrenched vehicles, the manoeuvering of furniture, and athletic pursuits such as US football or wrestling. Depending on the scenario, human push capability involves strength, weight, weight distribution, push angle, footwear/floor friction, and the friction between the upper body and the pushed object. Simple models are used to establish the relationships among these factors. PMID:16540441

  19. Disorders of Human Hemoglobin

    NASA Astrophysics Data System (ADS)

    Bank, Arthur; Mears, J. Gregory; Ramirez, Francesco

    1980-02-01

    Studies of the human hemoglobin system have provided new insights into the regulation of expression of a group of linked human genes, the ? -? -? globin gene complex in man. In particular, the thalassemia syndromes and related disorders of man are inherited anemias that provide mutations for the study of the regulation of globin gene expression. New methods, including restriction enzyme analysis and cloning of cellular DNA, have made it feasible to define more precisely the structure and organization of the globin genes in cellular DNA. Deletions of specific globin gene fragments have already been found in certain of these disorders and have been applied in prenatal diagnosis.

  20. Ayahuasca and human destiny.

    PubMed

    McKenna, Dennis J

    2005-06-01

    In this essay, the author shares his personal reflections gleaned from a lifetime of research with ayahuasca, and speculates on the societal, political, planetary, and evolutionary implications of humanity's aeons-old symbiosis with this shamanic plant. The thesis is developed that at this critical historical juncture, ayahuasca has developed a strategy to broadcast its message to a wider world--a reflection of the urgent need to avert global ecological catastrophe. While ayahuasca has much to teach us, the critical question is, will humanity hear it, and heed it, in time? PMID:16149337

  1. Biodemography of human ageing

    PubMed Central

    Vaupel, James W.

    2014-01-01

    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 to be constant across individuals and over time: it seems that death is being delayed because people are reaching old age in better health. Research by demographers, epidemiologists and other biomedical researchers suggests that further progress is likely to be made in advancing the frontier of survival — and healthy survival — to even greater ages. PMID:20336136

  2. Cardiovascular Deconditioning in Humans: Human Studies Core

    NASA Technical Reports Server (NTRS)

    Williams, Gordon

    1999-01-01

    Major cardiovascular problems, secondary to cardiovascular deconditioning, may occur on extended space missions. While it is generally assumed that the microgravity state is the primary cause of cardiovascular deconditioning, sleep deprivation and disruption of diurnal rhythms may also play an important role. Factors that could be modified by either or both of these perturbations include: autonomic function and short-term cardiovascular reflexes, vasoreactivity, circadian rhythm of cardiovascular hormones (specifically the renin-angiotensin system) and renal sodium handling and hormonal influences on that process, venous compliance, cardiac mass, and cardiac conduction processes. The purpose of the Human Studies Core is to provide the infrastructure to conduct human experiments which will allow for the assessment of the likely role of such factors in the space travel associated cardiovascular deconditioning process and to develop appropriate countermeasures. The Core takes advantage of a newly-created Intensive Physiologic Monitoring (IPM) Unit at the Brigham and Women's Hospital, Boston, MA, to perform these studies. The Core includes two general experimental protocols. The first protocol involves a head down tilt bed-rest study to simulate microgravity. The second protocol includes the addition of a disruption of circadian rhythms to the simulated microgravity environment. Before and after each of these environmental manipulations, the subjects will undergo acute stressors simulating changes in volume and/or stress, which could occur in space and on return to Earth. The subjects are maintained in a rigidly controlled environment with fixed light/dark cycles, activity pattern, and dietary intake of nutrients, fluids, ions and calories.

  3. Human Resources August 2011

    E-print Network

    Doran, Simon J.

    for taking appropriate action to achieve his/her targets. If an academic probationer discovers that it mightHuman Resources August 2011 GUIDELINES FOR ACADEMIC STAFF ON PROBATION 1 of 16 #12;1. Purpose & Scope 1.1 For the purpose of these guidelines the term 'academic' refers to all academic staff (as

  4. Mobility and Human Development

    Microsoft Academic Search

    Hein de Haas

    2009-01-01

    This paper argues that mobility and migration have always been an intrinsic part of human development. Migration can be considered as a fundamental capabilities-enhancing freedom itself. However, any meaningful understanding of migration needs to simultaneously analyse agency and structure. Rather than applying dichotomous classifications such as between forced and voluntary migration, it is more appropriate to conceive of a continuum

  5. Human megakaryocytic progenitor cells

    Microsoft Academic Search

    L. Kanz; G. W. Löhr; A. A. Fauser

    1987-01-01

    Summary Megakaryocytopoiesis represents one of several differentiation pathways that hematopoietic stem cells may enter. Cells representing intermediate stages of differentiation between pluripotent stem cells and maturing megakaryocytes are called megakaryocytic progenitor cells. They are identified in human bone marrow and peripheral blood by their ability to proliferate in culture (colony forming unit-megakaryocyte, CFU-M); at some point they lose the capacity

  6. Biotechnologies and Human Dignity

    ERIC Educational Resources Information Center

    Sweet, William; Masciulli, Joseph

    2011-01-01

    In this article, the authors review some contemporary cases where biotechnologies have been employed, where they have had global implications, and where there has been considerable debate. The authors argue that the concept of dignity, which lies at the center of such documents as the 2005 Universal Declaration on Bioethics and Human Rights, the…

  7. The Humanities, Unraveled

    ERIC Educational Resources Information Center

    Berube, Michael

    2013-01-01

    Graduate education in the humanities is in crisis. Every aspect, from the most specific details of the curriculum to the broadest questions about its purpose, is in crisis. It is a seamless garment of crisis: If one pulls on any one thread, the entire thing unravels. It is therefore exceptionally difficult to discuss any one aspect of graduate…

  8. Human Ecology: Curriculum Review.

    ERIC Educational Resources Information Center

    Bybee, Rodger W.

    1984-01-01

    Describes nine commercially available programs which represent one aspect or a portion of the human ecology theme. Other information supplied for each program includes: program objectives; methods of instruction; specific subjects, grade, and ability levels; materials produced and purchasable; program implementation; teacher preparation; program…

  9. Preeclampsia and human reproduction

    Microsoft Academic Search

    Pierre-Yves Robillard; Thomas C. Hulsey; Gustaaf A. Dekker; Gérard Chaouat

    2003-01-01

    Hypertensive disorders of pregnancy (HDP: pregnancy-induced hypertension, preeclampsia, eclampsia) affect approximately 10% of human births. Women are at increased risk for HDP during their first conception; and\\/or when the conception is with a new partner (new paternity); when conception occurs very shortly after the beginning of their sexual relationship. A primary cause of preeclampsia is the defect of the normal

  10. Futures of Human Communication.

    ERIC Educational Resources Information Center

    Harms, L. S.

    There are several research areas basic to the long-range future of human communications. Telecommunication and transportation offer the possiblity of two worldwide communications networks whose interrelationships need to be explored in terms of the needs of the individual, the community, and the world at large. Expanding possibilities of…

  11. Developing Human Resources.

    ERIC Educational Resources Information Center

    Nadler, Leonard

    This book attempts to capture the essence of a rapidly emerging field, that of Human Resource Development (HRD). HRD includes improving performance on the present job (training), preparing individuals for future but identifiable jobs within the organization (education), and helping individuals grow to meet future organizational growth…

  12. Humanities computing in Italy

    Microsoft Academic Search

    Antonio Zampolli

    1973-01-01

    1. Historical Introduction It is unnecessary to give more than a brief introduction here since the origins and the development of humanities computing activities and of computational linguistics hi Italy have already been described in previous articles (cf. A. Zampolli, 1967; U. Bortolini, C. Tagliavini, A. Zampolli, 1971). The present article is designed to cover development between 1968 and 1973,

  13. Human Appearance Change Detection

    Microsoft Academic Search

    Nagia M. Ghanem; Larry S. Davis

    2007-01-01

    We present a machine learning approach to detect changes in human appearance between instances of the same person that may be taken with different cameras, but over short periods of time. For each video sequence of the person, we approximately align each frame in the sequence and then generate a set of features that captures the differences between the two

  14. Human Aggression and Suicide

    ERIC Educational Resources Information Center

    Brown, Gerald L.; Goodwin, Frederick K

    1986-01-01

    The central nervous system transmitter serontonin may be altered in aggressive/impulsive and suicidal behaviors in humans. These reports are largely consistent with animal data, and constitute one of the most highly replicated set of findings in biological psychiatry. Suggests that some suicidal behavior may be a special kind of aggressive…

  15. TECHNOLOGIES FOR IMPROVING HUMAN

    E-print Network

    Loomis, Jack M.

    with blindness and deafness has been some forni of sensory substitution -allowing a remaining sense to take over the functions lost as the result of the sensory impairment. With visual loss, hearing and touch naturally take world. However, because unaided sensory substitution is only partially effective, humans have long

  16. Human waves in stadiums

    Microsoft Academic Search

    I. Farkas; D. Helbing; T. Vicsek

    2003-01-01

    Mexican wave first widely broadcasted during the 1986 World Cup held in Mexico, is a human wave moving along the stands of stadiums as one section of spectators stands up, arms lifting, then sits down as the next section does the same. Here we use variants of models originally developed for the description of excitable media to demonstrate that this

  17. Human Papilloma Virus Infections

    PubMed Central

    Wright, V. Cecil

    1989-01-01

    Genital warts are believed to be caused by human papilloma viruses and to be sexually transmitted. The viruses are classified by DNA types, which appear to cause different types of disease. The choice of treatment, and usually its success rate, vary according to the type of disease and its location. PMID:21248973

  18. Human DNA Repair Genes

    Microsoft Academic Search

    Richard D. Wood; Michael Mitchell; John Sgouros; Tomas Lindahl

    2001-01-01

    Cellular DNA is subjected to continual attack, both by reactive species inside cells and by environmental agents. Toxic and mutagenic consequences are minimized by distinct pathways of repair, and 130 known human DNA repair genes are described here. Notable features presently include four enzymes that can remove uracil from DNA, seven recombination genes related to RAD51, and many recently discovered

  19. Genetics of human heterotaxias

    Microsoft Academic Search

    Lirong Zhu; John W Belmont; Stephanie M Ware

    2006-01-01

    The past decade has seen remarkable advances in defining the molecular mechanisms underlying formation of the embryonic left right (LR) axis. This information is slowly transforming our understanding of human birth defects that are caused by disturbed LR axis patterning. Reversals, isomerisms, or segmental discordances of thoraco-abdominal organ position, that is, classic heterotaxy, clearly indicate embryonic disruption of normal LR

  20. Tackling Human Rights

    ERIC Educational Resources Information Center

    McLester, Susan

    2005-01-01

    In 2003, four high school students from the Tashkent International School in the capital city confronted the issue of their nation's human rights problems head on by researching the topic and publishing their findings on the Web. The site, "Uzbekistan: Opaque Reality," was created as an entry for the non-profit Global SchoolNet's Doors to…

  1. Ubiquitous human computing.

    PubMed

    Zittrain, Jonathan

    2008-10-28

    Ubiquitous computing means network connectivity everywhere, linking devices and systems as small as a drawing pin and as large as a worldwide product distribution chain. What could happen when people are so readily networked? This paper explores issues arising from two possible emerging models of ubiquitous human computing: fungible networked brainpower and collective personal vital sign monitoring. PMID:18672463

  2. Occupying the Digital Humanities

    ERIC Educational Resources Information Center

    Rice, Jeff

    2013-01-01

    This essay questions the digital humanities' dependence on interpretation and critique as strategies for reading and responding to texts. Instead, the essay proposes suggestion as a digital rhetorical practice, one that does not replace hermeneutics, but instead offers alternative ways to respond to texts. The essay uses the Occupy movement as an…

  3. Solving the human predicament

    Microsoft Academic Search

    Paul R. Ehrlich; Anne H. Ehrlich

    2012-01-01

    The authors offer an ecological frame of reference for political action to change the economic and social trends now deepening the human predicament: overpopulation and continuing population growth, overconsumption by rich societies, resource depletion, environmental degradation, and inequitable distribution of wealth within and between societies. Certain points often overlooked include: the demographic contribution to environmental deterioration; climate disruption, global toxification,

  4. Parasites and human evolution.

    PubMed

    Perry, George H

    2014-01-01

    Our understanding of human evolutionary and population history can be advanced by ecological and evolutionary studies of our parasites. Many parasites flourish only in the presence of very specific human behaviors and in specific habitats, are wholly dependent on us, and have evolved with us for thousands or millions of years. Therefore, by asking when and how we first acquired those parasites, under which environmental and cultural conditions we are the most susceptible, and how the parasites have evolved and adapted to us and we in response to them, we can gain considerable insight into our own evolutionary history. As examples, the tapeworm life cycle is dependent on our consumption of meat, the divergence of body and head lice may have been subsequent to the development of clothing, and malaria hyperendemicity may be associated with agriculture. Thus, the evolutionary and population histories of these parasites are likely intertwined with critical aspects of human biology and culture. Here I review the mechanics of these and multiple other parasite proxies for human evolutionary history and discuss how they currently complement our fossil, archeological, molecular, linguistic, historical, and ethnographic records. I also highlight potential future applications of this promising model for the field of evolutionary anthropology. PMID:25627083

  5. The Human Genome Project

    Microsoft Academic Search

    Maynard V. Olson

    1993-01-01

    The Human Genome Project in the United States is now well underway. Its programmatic direction was largely set by a National Research Council report issued in 1988. The broad framework supplied by this report has survived almost unchanged despite an upheaval in the technology of genome analysis. This upheaval has primarily affected physical and genetic mapping, the two dominant activities

  6. Radiation and human health

    Microsoft Academic Search

    J. W. Gofman; Karl Z. Morgan

    1983-01-01

    An attempt is made in the book to permit a layman to understand radiation and its effects. A basic presentations of radiation physics, the biology of human cancer, teratogenesis and genetics are considered excellent and concise reviews. A discussion on radiation studies is presented. The most extensive part of the book is a discussion of the risks of radiation-induced cancer.

  7. Radiation and human health

    Microsoft Academic Search

    Gofman

    1981-01-01

    A review of a book dealing with the estimation of human health effects of radiation is presented. Risk assessment for carcinogenesis is based on the author's own method of statistics so that standard statistical methods cannot be applied. Several examples of the author's fallacies are discussed in this book review. (KRM)

  8. Investing in Human Capital.

    ERIC Educational Resources Information Center

    Carnevale, Anthony P.

    2001-01-01

    Technology will not save us from scarce resource problems by creating "virtual schools." Technology is an expensive investment, adding value more than reducing costs. Social capital is the collateral necessary for human capital development. Our education system must consider its academic and cultural roles, not just provide foot soldiers for the…

  9. Humane Treatment of Animals.

    ERIC Educational Resources Information Center

    Dawson, Joan Smithey

    This booklet is designed to give teachers resource information about the humane treatment of and care for animals. The topics are presented as springboards for discussion and class activity. Topics include the care of dogs, cats, birds, horses, and fish; wildlife and ecological relationships; and careers with animals. Illustrations on some pages…

  10. Designers of Human Settlements

    ERIC Educational Resources Information Center

    Cliff, Ursula

    1976-01-01

    Reviewed herein are the ideas of nine men who have addressed themselves to the problems of human settlements in this century. The ideas reviewed include those of Arnold Toynbee, Lewis Mumford, Hassan Fathy, Buckminster Fuller, Constantinos Doxiadis, Charles Correa, Paul Mwaluko, Robert McNamara and John F. C. Turner. (BT)

  11. Human Subcutaneous Dirofilariasis, Russia

    PubMed Central

    Kartashev, Vladimir V.; Grandi, Giulio; Morchón, Rodrigo; Nagornii, Sergei A.; Karanis, Panagiotis; Simón, Fernando

    2007-01-01

    We report 14 cases of human subcutaneous dirofilariasis caused by Dirofilaria repens, diagnosed from February 2003 through July 2004, in patients from Rostov-on-Don, Russia. Serologic analysis showed evidence of high risk of exposure to D. repens. Surveillance studies on prevalence and prevention effectiveness of canine infection are needed to control this emerging zoonosis. PMID:17370533

  12. Immunogenetics Human immunogenetics

    E-print Network

    Alper, Chester A.

    complex NK natural killer T1D type 1 diabetes TAP transporters of antigenic peptides Human immunogenetics Opinion in Immunology 2004, 16:623­625 This review comes from a themed issue on Immunogenetics Edited (NK) cells, a major subset of the innate immune system, are the subject of two reviews in this section

  13. Human Development Student Modules.

    ERIC Educational Resources Information Center

    South Carolina State Dept. of Education, Columbia. Office of Vocational Education.

    This set of 61 student learning modules deals with various topics pertaining to human development. The modules, which are designed for use in performance-based vocational education programs, each contain the following components: an introduction for the student, a performance objective, a variety of learning activities, content information, a…

  14. Communicating with Virtual Humans.

    ERIC Educational Resources Information Center

    Thalmann, Nadia Magnenat

    The face is a small part of a human, but it plays an essential role in communication. An open hybrid system for facial animation is presented. It encapsulates a considerable amount of information regarding facial models, movements, expressions, emotions, and speech. The complex description of facial animation can be handled better by assigning…

  15. Towards International Humanism

    ERIC Educational Resources Information Center

    Huxley, Julian

    1971-01-01

    The basic task before the educational profession today is to study and understand the evolutionary-humanist revolution, to follow up its educational implications; and to enable as many as possible of the world's growing minds to be illuminated by its new vision of human destiny. (Author/JB)

  16. Assemble the Human Heart

    NSDL National Science Digital Library

    COSI

    2000-01-01

    In this online activity about anatomy, learners will drag and drop pieces of the heart into their proper positions and explore what function each part of the heart has. This activity is part of a rather extensive collection of activities and information surrounding the wonder of the human heart.

  17. Human Biology: Experimental.

    ERIC Educational Resources Information Center

    New York City Board of Education, Brooklyn, NY. Bureau of Curriculum Development.

    Education is a process of adapting to change, and the rate of change is especially rapid in science today. This curriculum in human biology is an alternative to the New York State courses in general and Regents biology, and it has been designed to focus on change from the standpoint of the urban student. It is designed to provide students with…

  18. Human Learning and Memory

    ERIC Educational Resources Information Center

    Lieberman, David A.

    2012-01-01

    This innovative textbook is the first to integrate learning and memory, behaviour, and cognition. It focuses on fascinating human research in both memory and learning (while also bringing in important animal studies) and brings the reader up to date with the latest developments in the subject. Students are encouraged to think critically: key…

  19. Human Balance System

    MedlinePLUS

    ... and vision problems, and difficulty with concentration and memory. What is balance? Balance is the ability to maintain the body’s center of mass over its base of support. 1 A properly functioning balance system allows humans to see clearly while moving, identify orientation with ...

  20. Human Memory: The Basics

    ERIC Educational Resources Information Center

    Martinez, Michael E.

    2010-01-01

    The human mind has two types of memory: short-term and long-term. In all types of learning, it is best to use that structure rather than to fight against it. One way to do that is to ensure that learners can fit new information into patterns that can be stored in and more easily retrieved from long-term memory.

  1. Television and Human Behavior.

    ERIC Educational Resources Information Center

    Comstock, George; And Others

    To compile a comprehensive review of English language scientific literature regarding the effects of television on human behavior, the authors of this book evaluated more than 2,500 books, articles, reports, and other documents. Rather than taking a traditional approach, the authors followed a new model for the retrieval and synthesis of…

  2. Visualising Human Dialog

    Microsoft Academic Search

    Annie Tat; M. Sheelagh T. Carpendale

    2002-01-01

    Human dialogue is so complex that definitively analysing patterns of conversation may well be impossible. Within a conversation, all the complexities and ambiguities of natural language exist and each speaker will have his\\/her own speech characteristics and moods. Examining these characteristics through text dialog can be a demanding cognitive task . One reason is because the whole conversation cannot be

  3. The Classics as Humanities

    ERIC Educational Resources Information Center

    Norton, Mary E.

    1975-01-01

    Classics may be taught as humanities to help students understand both the ancient and modern worlds. Literature taught in translation can acquaint students with these works and illuminate modern literature. Visual aids such as slides, photos, post cards, sculpture reproductions and maps may awaken student interest. (CK)

  4. Human Social Genomics

    PubMed Central

    Cole, Steven W.

    2014-01-01

    A growing literature in human social genomics has begun to analyze how everyday life circumstances influence human gene expression. Social-environmental conditions such as urbanity, low socioeconomic status, social isolation, social threat, and low or unstable social status have been found to associate with differential expression of hundreds of gene transcripts in leukocytes and diseased tissues such as metastatic cancers. In leukocytes, diverse types of social adversity evoke a common conserved transcriptional response to adversity (CTRA) characterized by increased expression of proinflammatory genes and decreased expression of genes involved in innate antiviral responses and antibody synthesis. Mechanistic analyses have mapped the neural “social signal transduction” pathways that stimulate CTRA gene expression in response to social threat and may contribute to social gradients in health. Research has also begun to analyze the functional genomics of optimal health and thriving. Two emerging opportunities now stand to revolutionize our understanding of the everyday life of the human genome: network genomics analyses examining how systems-level capabilities emerge from groups of individual socially sensitive genomes and near-real-time transcriptional biofeedback to empirically optimize individual well-being in the context of the unique genetic, geographic, historical, developmental, and social contexts that jointly shape the transcriptional realization of our innate human genomic potential for thriving. PMID:25166010

  5. Human-robot teaming

    Microsoft Academic Search

    Terrance M. Tierney; William J. Protzman; Brian Samples

    2005-01-01

    This presentation will provide program information, goals and objectives of the Technology for Human-Robot Interactions in Soldier-Robot Teaming (HRI) Army Technology Objective (ATO). The intent of this program is to develop and demonstrate an intelligent scaleable interface for mounted and dismounted control of ground and air unmanned systems. Currently in the Army there are unique interfaces developed by engineers for

  6. Quantitative human gait analysis

    Microsoft Academic Search

    Vlasta Zanchi; Vladan Papic; Mojmil Cecic

    2000-01-01

    In this paper, the methodology for normal gait recognition and estimation is described. Normal gait recognition is derived on the basis of kinematics data of the human locomotion system. Measurements were carried out and the data were processed and statistically analyzed.The procedure was done on a group of 20 students. Kinematics data have been presented in phase plane. Sets of

  7. POSTGRADUATE Arts,Humanities

    E-print Network

    O'Mahony, Donal E.

    Master in Social Work (M.S.W.) 104 M.Sc.Courses Applied Social Research 105 Child Protection and Welfare 107 Disability Studies 108 Drug and Alcohol Policy 110 M.Phil.Courses Social Work Research 111POSTGRADUATE COURSES 2012 Arts,Humanities & Social Sciences #12;Contents SCHOOL OF BUSINESS 4 Named

  8. Potatoes and Human Health

    Microsoft Academic Search

    Mary Ellen Camire; Stan Kubow; Danielle J. Donnelly

    2009-01-01

    The potato (Solanum tuberosum L.) tuber follows only rice and wheat in world importance as a food crop for human consumption. Cultivated potatoes have spread from the Andes of South America where they originated to 160 countries around the world. Consumption of fresh potatoes has declined while processed products have increased in popularity. As the potato becomes a staple in

  9. Urocortins in human reproduction

    Microsoft Academic Search

    Pasquale Florio; Wylie Vale; Felice Petraglia

    2004-01-01

    Data on biological effects and localization of corticotropin-releasing factor (CRF), a neuropeptide structurally and biologically related to urocortins, have triggered the study on expression of urocortins and their function in human reproductive tissues. Ovary, endometrium, placenta and fetal membranes (amnion and chorion), myometrium, and prostate are sources of urocortin 1 and, they also express urocortin binding sites (receptors and CRF-binding

  10. Humanizing the Workplace.

    ERIC Educational Resources Information Center

    Fairfield, Roy P., Ed.

    A series of essays discussing ideas about humanizing work are presented in the document. Three major sections divide the essays, and each includes a preface with comments suggesting the central focus and questions with which the authors are concerned. The first section deals with the history, philosophy, and issues related to work and contains…

  11. Human Specimen Resources | Resources

    Cancer.gov

    The Pathology Investigation and Resources Branch support programs that collect and distribute human biospecimens programs through grant funding. These programs make high-quality tissue and associated data available to the research community. Listed below is a description of current PIRB supported programs.

  12. Fighting for Human Rights

    ERIC Educational Resources Information Center

    Ong, Bao

    2011-01-01

    Speak Truth To Power consists of 17 teacher-developed lessons based on the stories of rights advocates from all over the world. The lessons were created for sixth-through 12th-grade students, and have come to New York schools thanks to the Robert F. Kennedy Center for Justice and Human Rights and the New York State United Teachers union. Speak…

  13. The Human Orrery

    Microsoft Academic Search

    M. E. Bailey; A. A. Christou; D. J. Asher

    2005-01-01

    The Human Orrery is a dynamic model of the solar system, where people play the role of the moving planets. The users' interactions with the model lead to greater awareness of their place in space and understanding of our planet's changing position with time. It is an innovative concept, the first example in the world to show with precision the

  14. The Human Phenome Project

    Microsoft Academic Search

    Chiara Sabatti; Nelson Freimer

    2003-01-01

    A principal goal of genetic research is to identify specific genotypes that are associated with human phenotypes. It will soon be possible to conduct genome-wide genotyping on a massive scale. Our cur- rent approaches for defining and assaying phenotypes may be inadequate for making optimal use of such genotypic data. We propose an international effort to create phenomic databases, that

  15. Hydroxytyrosol Disposition in Humans

    Microsoft Academic Search

    Elisabet Miro-Casas; Maria-Isabel Covas; Magi Farre; Montserrat Fito; Jordi Ortuno; Tanja Weinbrenner; Pere Roset; Rafael de la Torre

    Background: Animal and in vitro studies suggest that phenolic compounds in virgin olive oil are effective antioxidants. In animal and in vitro studies, hydroxyty- rosol and its metabolites have been shown to be strong antioxidants. One of the prerequisites to assess their in vivo physiologic significance is to determine their pres- ence in human plasma. Methods: We developed an analytical

  16. Therapeutic Human Papillomavirus Vaccination

    Microsoft Academic Search

    Andreas E. Albers; Andreas M. Kaufmann

    2009-01-01

    Despite impressive progress in prevention and therapy of premalignant and malignant dysplasia the worldwide burden of cancer is relatively unchanged. Supplementation of the therapeutic arsenal by immunotherapeutic methods would have the potential to make a significant impact. Dysplastic lesions and cancer of the cervix show strong association with human papillomaviruses (HPV), as do tumours of other mucosal epithelia like squamous

  17. Human Vaccines & Immunotherapeutics

    PubMed Central

    Riedmann, Eva M

    2013-01-01

    DNA vaccine for T1D promising in the clinic HPV vaccines halved infections in US teenage girls Modified DC immunotherapy against melanoma New study looks at clinical severity of human H7N9 infections Prevnar vaccines are valuable for healthcare systems GAPVAC: New consortium in the fight of brain cancer Cytomegalovirus vaccine to enter phase 3 Malaria vaccination using chemically attenuated parasites

  18. HHMI Human Embryonic Development

    NSDL National Science Digital Library

    HHMI (Howard Hughes Medical Institute)

    2006-12-01

    This video provides a talk and video illustration of the anatomical changes during human embryonic development. A clever feature of the video is that it compares the size of the growing fetus to a known shape to be able to draw comparisons. This is presented by HHMI's Biointeractive Series.

  19. Neurobiology and the Humanities

    PubMed Central

    Zeki, Semir

    2014-01-01

    Can the arts and humanities contribute significantly to the study of the brain? Similar brain processes are involved in humanistic and scientific inference, and in this essay, I argue that conclusions reached by one are relevant to the other. PMID:25277451

  20. Basic human factors considerations

    Microsoft Academic Search

    R. J. Nertney; D. L. Fillmore

    1985-01-01

    Models and concepts for analyzing the human element in working programs and systems are introduced. The method of attack is a functional one based on analysis of the work to be done (job-task analysis). Based on the results of the job-task analysis, psychological and physiological requirements and criteria can be defined for the system.

  1. Basic human factors considerations

    SciTech Connect

    Nertney, R.J.; Fillmore, D.L.

    1985-12-01

    Models and concepts for analyzing the human element in working programs and systems are introduced. The method of attack is a functional one based on analysis of the work to be done (job-task analysis). Based on the results of the job-task analysis, psychological and physiological requirements and criteria can be defined for the system.

  2. Reconsidering Human Performance Technology

    ERIC Educational Resources Information Center

    Jang, Hwan Young

    2008-01-01

    This article discusses three perceived challenges in the field of human performance technology: a missing link from training to performance, limitations in gap analysis and cause analysis, and a lack of attention to business and organization performance. It then provides possible alternatives for each issue, such as instructional system…

  3. Human social genomics.

    PubMed

    Cole, Steven W

    2014-08-01

    A growing literature in human social genomics has begun to analyze how everyday life circumstances influence human gene expression. Social-environmental conditions such as urbanity, low socioeconomic status, social isolation, social threat, and low or unstable social status have been found to associate with differential expression of hundreds of gene transcripts in leukocytes and diseased tissues such as metastatic cancers. In leukocytes, diverse types of social adversity evoke a common conserved transcriptional response to adversity (CTRA) characterized by increased expression of proinflammatory genes and decreased expression of genes involved in innate antiviral responses and antibody synthesis. Mechanistic analyses have mapped the neural "social signal transduction" pathways that stimulate CTRA gene expression in response to social threat and may contribute to social gradients in health. Research has also begun to analyze the functional genomics of optimal health and thriving. Two emerging opportunities now stand to revolutionize our understanding of the everyday life of the human genome: network genomics analyses examining how systems-level capabilities emerge from groups of individual socially sensitive genomes and near-real-time transcriptional biofeedback to empirically optimize individual well-being in the context of the unique genetic, geographic, historical, developmental, and social contexts that jointly shape the transcriptional realization of our innate human genomic potential for thriving. PMID:25166010

  4. Human-Robot Interaction

    NASA Technical Reports Server (NTRS)

    Sandor, Aniko; Cross, E. Vincent, II; Chang, Mai Lee

    2015-01-01

    Human-robot interaction (HRI) is a discipline investigating the factors affecting the interactions between humans and robots. It is important to evaluate how the design of interfaces affect the human's ability to perform tasks effectively and efficiently when working with a robot. By understanding the effects of interface design on human performance, workload, and situation awareness, interfaces can be developed to appropriately support the human in performing tasks with minimal errors and with appropriate interaction time and effort. Thus, the results of research on human-robot interfaces have direct implications for the design of robotic systems. For efficient and effective remote navigation of a rover, a human operator needs to be aware of the robot's environment. However, during teleoperation, operators may get information about the environment only through a robot's front-mounted camera causing a keyhole effect. The keyhole effect reduces situation awareness which may manifest in navigation issues such as higher number of collisions, missing critical aspects of the environment, or reduced speed. One way to compensate for the keyhole effect and the ambiguities operators experience when they teleoperate a robot is adding multiple cameras and including the robot chassis in the camera view. Augmented reality, such as overlays, can also enhance the way a person sees objects in the environment or in camera views by making them more visible. Scenes can be augmented with integrated telemetry, procedures, or map information. Furthermore, the addition of an exocentric (i.e., third-person) field of view from a camera placed in the robot's environment may provide operators with the additional information needed to gain spatial awareness of the robot. Two research studies investigated possible mitigation approaches to address the keyhole effect: 1) combining the inclusion of the robot chassis in the camera view with augmented reality overlays, and 2) modifying the camera frame of reference. The first study investigated the effects of inclusion and exclusion of the robot chassis along with superimposing a simple arrow overlay onto the video feed of operator task performance during teleoperation of a mobile robot in a driving task. In this study, the front half of the robot chassis was made visible through the use of three cameras, two side-facing and one forward-facing. The purpose of the second study was to compare operator performance when teleoperating a robot from an egocentric-only and combined (egocentric plus exocentric camera) view. Camera view parameters that are found to be beneficial in these laboratory experiments can be implemented on NASA rovers and tested in a real-world driving and navigation scenario on-site at the Johnson Space Center.

  5. HUMAN/VECTOR RELATIONSHIPS DURING HUMAN AFRICAN TRYPANOSOMIASIS: INITIAL SCREENING OF IMMUNOGENIC SALIVARY

    E-print Network

    Paris-Sud XI, Université de

    HUMAN/VECTOR RELATIONSHIPS DURING HUMAN AFRICAN TRYPANOSOMIASIS: INITIAL SCREENING OF IMMUNOGENIC immunogenic proteins in humans residing in an area endemic for human African trypanosomiasis in the Democratic

  6. Helicopter Human Factors

    NASA Technical Reports Server (NTRS)

    Hart, Sandra G.; Sridhar, Banavar (Technical Monitor)

    1995-01-01

    Even under optimal conditions, helicopter flight is a most demanding form of human-machine interaction, imposing continuous manual, visual, communications, and mental demands on pilots. It is made even more challenging by small margins for error created by the close proximity of terrain in NOE flight and missions flown at night and in low visibility. Although technology advances have satisfied some current and proposed requirements, hardware solutions alone are not sufficient to ensure acceptable system performance and pilot workload. However, human factors data needed to improve the design and use of helicopters lag behind advances in sensor, display, and control technology. Thus, it is difficult for designers to consider human capabilities and limitations when making design decisions. This results in costly accidents, design mistakes, unrealistic mission requirements, excessive training costs, and challenge human adaptability. NASA, in collaboration with DOD, industry, and academia, has initiated a program of research to develop scientific data bases and design principles to improve the pilot/vehicle interface, optimize training time and cost, and maintain pilot workload and system performance at an acceptable level. Work performed at Ames, and by other research laboratories, will be reviewed to summarize the most critical helicopter human factors problems and the results of research that has been performed to: (1) Quantify/model pilots use of visual cues for vehicle control; (2) Improve pilots' performance with helmet displays of thermal imagery and night vision goggles for situation awareness and vehicle control; (3) Model the processes by which pilots encode maps and compare them to the visual scene to develop perceptually and cognitively compatible electronic map formats; (4) Evaluate the use of spatially localized auditory displays for geographical orientation, target localization, radio frequency separation; (5) Develop and flight test control/display concepts; (6) Quantify, model, predict, and improve pilots, workload-management strategies; and (7) Design computer-game trainers to reduce training time and cost.

  7. Re-Thinking the Human: Heidegger, Fundamental Ontology, and Humanism

    Microsoft Academic Search

    Gavin Rae

    2010-01-01

    This essay engages with Heidegger’s attempt to re-think the human being. It shows that Heidegger re-thinks the human being\\u000a by challenging the way the human being has been thought, and the mode of thinking traditionally used to think about the human\\u000a being. I spend significant time discussing Heidegger’s attempt before, in the final section, asking some critical questions\\u000a of Heidegger’s

  8. Human Computing and Machine Understanding of Human Behavior: A Survey

    Microsoft Academic Search

    Maja Pantic; Alex Pentland; Anton Nijholt; Thomas S. Huang; Th. S. Huang

    2007-01-01

    A widely accepted prediction is that computing will move to the background, weaving itself into the fabric of our everyday\\u000a living spaces and projecting the human user into the foreground. If this prediction is to come true, then next generation\\u000a computing should be about anticipatory user interfaces that should be human-centered, built for humans based on human models.\\u000a They should

  9. HUMAN NUTRITION -FUNCTIONAL FOODS KNL030 Human Nutrition -Functional Foods

    E-print Network

    HUMAN NUTRITION - FUNCTIONAL FOODS KNL030 Human Nutrition - Functional Foods Poäng: 5.0 Betygskala grupparbeten. Litteratur: Garrow, J.S.; James, W.P.T.: Human nutrition and dietetics, 9th ed, Churchill Livingstone eller Whitney, E.S., Rolfes, S.R.: Understanding nutrition, 8th ed, 1999, West Publishing Company

  10. Do international human rights treaties improve respect for human rights?

    Microsoft Academic Search

    Eric Neumayer

    2004-01-01

    After the non-binding Universal Declaration of Human Rights, many global and regional human rights treaties have been concluded. Critics argue that these are unlikely to have made any actual difference in reality. Others contend that international regimes can improve respect for human rights in state parties, particularly in more democratic countries or countries with a strong civil society devoted to

  11. Do International Human Rights Treaties Improve Respect for Human Rights?

    Microsoft Academic Search

    Eric Neumayer

    2005-01-01

    After the nonbinding Universal Declaration of Human Rights, many global and regional human rights treaties have been concluded. Critics argue that these are unlikely to have made any actual difference in reality. Others contend that international regimes can improve respect for human rights in state parties, particularly in more democratic countries or countries with a strong civil society devoted to

  12. Dengue Virus Tropism in Humanized Mice Recapitulates Human Dengue Fever

    Microsoft Academic Search

    Javier Mota; Rebeca Rico-Hesse

    2011-01-01

    Animal models of dengue virus disease have been very difficult to develop because of the virus' specificity for infection and replication in certain human cells. We developed a model of dengue fever in immunodeficient mice transplanted with human stem cells from umbilical cord blood. These mice show measurable signs of dengue disease as in humans (fever, viremia, erythema and thrombocytopenia),

  13. The optics of human skin: Aspects important for human health

    Microsoft Academic Search

    Kristian P. Nielsen; Lu Zhao; Jakob J. Stamnes; Knut Stamnes; Johan Moan

    Human health can be strongly influenced by exposure to solar radiation. Interactions relevant for health take place mainly in the skin. In this context the optics of human skin is of the utmost importance. Reflection, scattering and absorption are the optical properties affecting the nature of these interactions. By combining a bio-optical model of human skin with advanced radiative transfer

  14. Reprogramming of Human Somatic Cells Using Human and Animal Oocytes

    Microsoft Academic Search

    Young Chung; Colin E. Bishop; Nathan R. Treff; Stephen J. Walker; Vladislav M. Sandler; Sandy Becker; Irina Klimanskaya; Wan-Song Wun; Randall Dunn; Rebecca M. Hall; Jing Su; Shi-Jiang Lu; Marc Maserati; Young-Ho Choi; Richard Scott; Anthony Atala; Ralph Dittman; Robert Lanza

    2009-01-01

    There is renewed interest in using animal oocytes to reprogram human somatic cells. Here we compare the re- programming of human somatic nuclei using oocytes obtained from animal and human sources. Comparative analysis of gene expression in morula-stage embryos was carried out using single-embryo transcriptome am- plification and global gene expression analyses. Genomic DNA fingerprinting and PCR analysis confirmed that

  15. Human leadership approaches to hybrid human\\/robot teams

    Microsoft Academic Search

    Ben E. Nizette; Changbin Yu

    2011-01-01

    In this paper we examine work mapping human leadership styles to human control of robots. This work is extended to the context of a human leader with a team of robots in navigation and exploration scenarios. Particular leadership styles are selected as being appropriate for this category of scenario and specific implementations are detailed. We conclude by discussing a set

  16. Climate Change and Human Health

    NSDL National Science Digital Library

    2011-05-02

    Learn how global climate change affects human health in this interactive activity adapted from A Human Health Perspective: On Climate Change by the National Institute of Environmental Health Sciences.

  17. Human body animation: a survey

    Microsoft Academic Search

    Dani Tost; Xavier Pueyo

    1988-01-01

    A survey of human body animation is presented dealing with its geometrical representation, motion control techniques and rendering. A classification of human body animation systems is presented according to different criteria.

  18. Natural Human-Computer Interaction

    NASA Astrophysics Data System (ADS)

    D'Amico, Gianpaolo; Del Bimbo, Alberto; Dini, Fabrizio; Landucci, Lea; Torpei, Nicola

    Research work in relation to Natural Human-Computer Interaction concerns the theorization and development of systems that understand and recognize human communicative actions in order to engage people in a dialogue between them and their surroundings.

  19. HUMAN GROSS ANATOMY ANTH 695

    E-print Network

    Auerbach, Benjamin M.

    1 HUMAN GROSS ANATOMY ANTH 695 THE UNIVERSITY OF TENNESSEE Instructor in Anatomy Lecture Series Fridays: 12:20 PM ­ 1:10 PM lectures: 33 ALUMNI MEMORIAL BUILDING Course description: Human Gross Anatomy

  20. DEMONSTRATION OF HUMAN EXPOSURE TOOLS

    EPA Science Inventory

    The Human Exposure and Atmospheric Sciences Division (HEASD) of the National Exposure Research Laboratory (NERL) conducts research on exposure measurements, human activity patterns, exposure and dose models, and cumulative exposures critical for the Agency to make scientificall...

  1. Two approaches to human rights

    E-print Network

    Holland, Sean Jamison

    2009-01-01

    Contemporary philosophy of human rights is dominated by two seemingly opposed approaches. This dissertation is concerned with the choice between them. The traditional approach to human rights is characterized by the belief ...

  2. Human Development Report 2006

    NSDL National Science Digital Library

    2006-01-01

    Every year, many policy specialists and government officials eagerly await the annual Human Development Report issued by the United Nations Development Programme. Released in early November 2006, this yearâ??s report was primarily focused on the issue of water, and they remarked that, â??unclean water is an immeasurably greater threat to human security that violent conflict.â? Within its 440 page, the report investigates the underlying causes and consequences of this crisis, along with arguing for â??a concerted drive to achieve water and sanitation for all through national strategies and a global plan of action.â? Along with significant appendices, the report also contains special contributions from President Jimmy Carter, Gordon Brown, and UN Secretary General Kofi Annan.

  3. Human herpesvirus 8.

    PubMed

    Martinelli, Paul T; Tyring, Stephen K

    2002-04-01

    Human herpesvirus 8 (HHV 8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV) is a g2 herpesvirus and the most recently identified human tumor virus. HHV 8 has been consistently implicated in the pathogenesis of all clinical variants of Kaposi's sarcoma, as well as in the plasma cell variant of multicentric Castleman's disease and primary effusion lymphomas. Pathogenicity of the virus is increased in the host who is immunosuppressed, either iatrogenically or through H1V-1 infection. The HHV 8 genome contains several homologues of cellular genes that regulate cell growth and differentiation, and the exact mechanisms of the virus' oncogenicity using molecular piracy are still being investigated and elucidated. In this article, the authors review the epidemiology, transmission, clinical manifestations, and molecular genetics of HHV 8 infection and provide a summary of the current treatment modalities available to the clinician. PMID:12120444

  4. Geology and Human Health

    NSDL National Science Digital Library

    The link between geology and human health may not seem obvious, but it many ways geology can affect public health in a variety of crucial ways. Certainly, the relationship between geological factors and water and air quality is one that continues to interest policy makers and others. This site explores these issues, and it was created by the people at Carleton College's Professional Development for Geoscience Faculty initiative. Here visitors can make use of a wide range of educational and supporting materials, including classroom activities, key visualizations, and collections of external links. First-time users may wish to start at the "Resources for Educators" area, which includes a brief overview titled "Essential components of geology and human health" and several helpful posters. The remaining materials can be viewed in sections that include "Bookshelf", "Visualizations", and "Internet Resources".

  5. How Did Humans Evolve?

    NSDL National Science Digital Library

    In this lesson, students learn about the process of human evolution by interacting with a Web activity and examining possible hominid family trees. With this hands-on approach, students become responsible for their own learning and are better able to see connections between ideas and remember what they learn. In an activity called Fossil Finding, students will study four famous fossil groups and learn how scientists interpret them to explain human evolution. Students will understand how fossil evidence can be used to describe ancient life forms, learn about different kinds of fossil evidence, and how paleontologists compare information from different fossil finds to learn more about ancient life forms. In the second activity students will study three possible hominid family trees and examine why they are different. Each activity has a list of objectives and links to detailed instruction. The lesson also offers links to an assessment rubric, the national science standards for the lesson, and additional activities.

  6. Posthumanism: beyond humanism?

    PubMed

    Valera, Luca

    2014-01-01

    The focal point of posthumanism consists not as such in an a-critical acceptance of the technological promises - like there is for transhumanism - but in a total contamination and hybridization of human beings with other living beings and machines (these are the two main forms of contamination). The change of perspective untaken by posthumanism would be, thus, a paradigmatic shift in anthropology. As with ecologism, posthumanism, in order to obtain total contamination and man's openness to otherness, proposes the elimination and the fluidification of boundaries, thus even denying man's identity, and, with it, the very possibility of openness. However, by denying the identity, one denies the condition of possibility of thought, just as it has been manifested in history until now: hence we understand how, primarily, posthumanism is not configured as an adequate philosophical reflection, but as a narrative that takes origin from certain requirements, which are eminently human, and that discloses its deeply anthropogenic roots. PMID:25684386

  7. Maine Humanities Council

    NSDL National Science Digital Library

    Formed as a private nonprofit organization, the Maine Humanities Council (MHC) "promotes strong communities and informed citizens by providing Mainers with opportunities to explore the power and pleasure of ideas." Their work is supported by volunteer board members, and their projects include programs to promote reading and writing, guest lectures around the state, and online newsletters and discussion groups. In the "Programs" area, visitors can learn about these programs, and educators can check out the resources created especially for them. The "Connections" area contains links to their thoughtful blog, their "Humanities on Demand" podcasts, and their periodic newsletter "Synapse", which deals with medicine and literature. The podcasts are quite fun, and they include "Franco-American Women's Words in Maine" and a talk by Professor Dianne Sadoff of Rutgers University on Middlemarch, by George Eliot.

  8. [Human dignity revisited].

    PubMed

    Pereira-Menaut, Antonio Carlos; Pereira Sáez, Carolina

    2014-01-01

    Since World War II, human dignity has made its way into many constitutions, bills of rights and international treaties. As its roots can be traced easily back to the Judeo-Christian tradition, and, later on, to the influential Kantian vision, dignity cannot be deemed an entirely new concept. For the same token, it cannot be said that dignity has been entirely alien to the legal realm till 1945. On the other hand, the latest philosophical and anthropological trends, as well as the politicisation of the human being, along with some recent advances in biotechnologies, help to explain its growing presence in the legal world. However, these authors suggest that writing down dignity in legal texts does not fully settle its meaning, not even if such texts are constitutions, and the fact remains that its presence in the judicial reasoning does not always imply being the ratio decidendi, as the study of some relevant judicial decisions shows. PMID:25329413

  9. BBC: Human Body & Mind

    NSDL National Science Digital Library

    2012-07-06

    The BBC has created this fine site to provide the curious visitor with a plethora of insights into the relationship between the human body and mind. In the Body section, visitors can take on a number of fun challenges in order to learn more about the muscles, skeleton, and the nervous system. Moving on, The Mind area contains a range of self-guided surveys that explore human emotion, memory retention, and a number of other subjects. For those concerned about sleep, the Sleep section contains information on sleep problems, sleep advice, and a well-developed section titled "Why do we sleep?" One particularly fun area here is the "Can You Compete Under Pressure?" challenge, which is hosted by world-renowned athlete Michael Johnson. The challenge takes 20 minutes and visitors who complete the challenge will learn a great deal about their own ability to perform under pressure.

  10. Democracy and Human Rights

    NSDL National Science Digital Library

    Maintained by the US Department of State's Office of International Information Programs (OIIP), formerly the USIA, this site is among the four US Policy topics covered in depth on the OIIP site. The Democracy and Human Rights site contains fewer resources than the International Security site, and in fact, the first headline links to the latter. The site offers access to several journals off the front page -- Criminal Justice in the United States, Accountability in Government, and Towards a Community of Democracies -- but the bulk of the site's material is divided into two sections, Democracy and Human Rights. Each contains policy documents, in-depth looks at selected issues, links to other resources, and more.

  11. Visible Human Server

    NSDL National Science Digital Library

    This Web site from the Swiss Federal Institute of Technology allows users to view three dimensional models of human anatomy. A free registration allows users to log on and fully access the site, but there are some sample demonstrations available without registration. When visiting the site, you can view, rotate, and extract cross sections from the anatomical models, or build your own anatomic model by choosing the structures of interest. The site works best with Internet Explorer 5 and the latest version of Microsoft Java VM. The site provides how-to files that are extremely helpful for new users. This is certainly a site for those studying human anatomy, but it is a cool site that may also appeal to others. This site is also reviewed in the April 5, 2002 NSDL Life Sciences Report.

  12. Human Endothelial Progenitor Cells

    PubMed Central

    Yoder, Mervin C.

    2012-01-01

    Human endothelial progenitor cells (EPCs) have been generally defined as circulating cells that express a variety of cell surface markers similar to those expressed by vascular endothelial cells, adhere to endothelium at sites of hypoxia/ischemia, and participate in new vessel formation. Although no specific marker for an EPC has been identified, a panel of markers has been consistently used as a surrogate marker for cells displaying the vascular regenerative properties of the putative EPC. However, it is now clear that a host of hematopoietic and vascular endothelial subsets display the same panel of antigens and can only be discriminated by an extensive gene expression analysis or use of a variety of functional assays that are not often applied. This article reviews our current understanding of the many cell subsets that constitute the term EPC and provides a concluding perspective as to the various roles played by these circulating or resident cells in vessel repair and regeneration in human subjects. PMID:22762017

  13. Human Development Report

    NSDL National Science Digital Library

    1999-01-01

    Released on Monday July 12, the tenth edition of the United Nation Development Programme's (UNDP) Human Development Report has garnered considerable attention from the international press all week. The report ranks 174 countries on quality of life indicators such as life expectancy, wealth, and literacy, ranking Canada at the top and Sierra Leone at the bottom. The report pays particular attention to the opportunities and dangers of globalization. Although living conditions in almost all countries have improved over the last ten years, according to the report, economic inequalities have reached "grotesque" proportions, "with the richest fifth of humanity enjoying more than 85% of total gross domestic product and the poorest fifth only 1%." Users can download the full text and statistical tables of the report by chapter at the UNDP site. Additional resources include an Online Newsroom, which contains a press kit, author information, early reviews, and a feature on the HDR team.

  14. Hyaluronan in human malignancies

    SciTech Connect

    Sironen, R.K. [Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland) [Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland); Department of Pathology, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio (Finland); Tammi, M.; Tammi, R. [Institute of Biomedicine, Anatomy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland)] [Institute of Biomedicine, Anatomy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland); Auvinen, P.K. [Department of Oncology, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio (Finland)] [Department of Oncology, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio (Finland); Anttila, M. [Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland) [Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland); Department of Gynecology and Obstetrics, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio (Finland); Kosma, V-M., E-mail: Veli-Matti.Kosma@uef.fi [Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio (Finland); Department of Pathology, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio (Finland)

    2011-02-15

    Hyaluronan, a major macropolysaccharide in the extracellular matrix of connective tissues, is intimately involved in the biology of cancer. Hyaluronan accumulates into the stroma of various human tumors and modulates intracellular signaling pathways, cell proliferation, motility and invasive properties of malignant cells. Experimental and clinicopathological evidence highlights the importance of hyaluronan in tumor growth and metastasis. A high stromal hyaluronan content is associated with poorly differentiated tumors and aggressive clinical behavior in human adenocarcinomas. Instead, the squamous cell carcinomas and malignant melanomas tend to have a reduced hyaluronan content. In addition to the stroma-cancer cell interaction, hyaluronan can influence stromal cell recruitment, tumor angiogenesis and epithelial-mesenchymal transition. Hyaluronan receptors, hyaluronan synthases and hyaluronan degrading enzymes, hyaluronidases, are involved in the modulation of cancer progression, depending on the tumor type. Furthermore, intracellular signaling and angiogenesis are affected by the degradation products of hyaluronan. Hyaluronan has also therapeutic implications since it is involved in multidrug resistance.

  15. United Nations: Human Rights

    NSDL National Science Digital Library

    How does the United Nations work to protect human rights? This subject-specific website provides information on the various offices, officials, policy initiatives, and actions related to this important agenda. There are five main sections to the site: UN Bodies, Thematic Issues, International Courts and Tribunals, Other Resources, and Past Conferences. The UN Bodies section contains information about the UN Human Rights Council, its various charters, treaties, and more. Thematic Issues is another great feature, offering detailed information on the Secretary-General's Campaign to End Violence Against Women as well as the UNâ??s Permanent Forum on Indigenous Issues. News items from around the world can be found on the right-hand side of the page, effectively covering everything from Sri Lankan ethnic minority groups to ongoing conflicts in Pakistan.

  16. Human Body Maps

    NSDL National Science Digital Library

    The human body is quite a wonder, and anyone with an interest in human anatomy and related topics will find this site quite useful. Visitors can get started by scrolling over a male or female body to learn more about the various body systems. There's a body keyword search engine here that is most useful. On the left-hand side of the page, visitors can use the demonstration section to rotate the bodies around and also look into different layers of the models provided here. The site also features embedded links to other resources that complement the interactive models. Visitors shouldn't miss the Video Tour area, which provides a great way to learn about all of the features here. This resource is appropriate for all ages, and it could be effectively used in a number of anatomy or physiology courses at the college level.

  17. Humbul Humanities Hub

    NSDL National Science Digital Library

    Funded by the Joint Information Systems Committee and hosted by the University of Oxford, the Humbul Humanities Hub is a service of the Resource Discovery Network. The site is geared towards meeting the needs of the humanities community and includes information in areas ranging from language and literature, to American studies, to archaeology, to philosophy. Furthermore, this site contains a searchable archive with links to various museums and libraries. During its nascent stage, this site was covered in the Scout Report's July 22, 1994 edition. However, since then, the site has added geography, education, sport, and tourism/leisure in order to ensure that interdisciplinary subjects are adequately covered. These additions give its visitors greater flexibility and diversity in deciding what to search for and how to conduct a search.

  18. Human action in a Genomic Era: debates on human nature.

    PubMed

    Rotondaro, Tatiana Gomes

    2009-01-01

    The supposed properties of 'genes' have led natural scientists to claim authority to explain the reasons of human action, behavior, and even human nature, which has traditionally been the object of study of the humanities. The aim of this paper is to discuss the possibilities of sociological theory dealing with the biological reductionism that establishes the strict articulation between 'human nature' and 'human action', presented in several speeches and papers by scientists and journalists and supported by features of 'genes'. I intend to argue that sociological theories may broaden their scope of analysis by encompassing biological dimensions, which does not necessarily mean adopting a biological reductionist approach. PMID:19824336

  19. Hypothermia protects human neurons

    PubMed Central

    Antonic, Ana; Dottori, Mirella; Leung, Jessie; Sidon, Kate; Batchelor, Peter E; Wilson, William; Macleod, Malcolm R; Howells, David W

    2014-01-01

    Background and Aims Hypothermia provides neuroprotection after cardiac arrest, hypoxic-ischemic encephalopathy, and in animal models of ischemic stroke. However, as drug development for stroke has been beset by translational failure, we sought additional evidence that hypothermia protects human neurons against ischemic injury. Methods Human embryonic stem cells were cultured and differentiated to provide a source of neurons expressing ? III tubulin, microtubule-associated protein 2, and the Neuronal Nuclei antigen. Oxygen deprivation, oxygen-glucose deprivation, and H2O2-induced oxidative stress were used to induce relevant injury. Results Hypothermia to 33°C protected these human neurons against H2O2-induced oxidative stress reducing lactate dehydrogenase release and Terminal deoxynucleotidyl transferase dUTP nick end labeling-staining by 53% (P???0·0001; 95% confidence interval 34·8–71·04) and 42% (P???0·0001; 95% confidence interval 27·5–56·6), respectively, after 24?h in culture. Hypothermia provided similar protection against oxygen-glucose deprivation (42%, P???0·001, 95% confidence interval 18·3–71·3 and 26%, P???0·001; 95% confidence interval 12·4–52·2, respectively) but provided no protection against oxygen deprivation alone. Protection (21%) persisted against H2O2-induced oxidative stress even when hypothermia was initiated six-hours after onset of injury (P???0·05; 95% confidence interval 0·57–43·1). Conclusion We conclude that hypothermia protects stem cell-derived human neurons against insults relevant to stroke over a clinically relevant time frame. Protection against H2O2-induced injury and combined oxygen and glucose deprivation but not against oxygen deprivation alone suggests an interaction in which protection benefits from reduction in available glucose under some but not all circumstances. PMID:24393199

  20. Human renin inhibiting dipeptide.

    PubMed

    Toda, N; Miyazaki, M; Etoh, Y; Kubota, T; Iizuka, K

    1986-10-01

    KRI-1177, a dipeptide containing nor-statine inhibited renin activity in human and Japanese monkey plasma to a markedly greater extent than that in dog, rabbit and rat plasma. The systemic blood pressure of anesthetized monkeys was lowered by intravenous injections of this compound which also reduced plasma renin activity and concentration of angiotensins. KRI-1177 appears to selectively inhibit primate renin activity, thereby producing hypotension. PMID:3536533

  1. Human Vaccines & Immunotherapeutics: News

    PubMed Central

    Riedmann, Eva M.

    2013-01-01

    Oncolytic vaccinia virus vaccine: Promising in liver cancer patients FDA panel endorses quadrivalent influenza vaccines Approval for the first meningitis B vaccine Stallergenes seeks FDA approval for sublingual grass-pollen allergy tablet Live-attenuated dengue vaccine promising in Phase 1 GAVI funds HPV vaccines for girls in developing countries First human trials for new superantigen bioterrorism vaccine Hexyon hexavalent pediatric vaccine recommended for approval

  2. Book Review: Human Radiosensitivity

    SciTech Connect

    Morgan, William F.

    2013-11-01

    This well written report reviews the evidence for variation in human sensitivity to ionizing radiation from epidemiological, clinical, animal, and experimental studies. The report also considers the mechanism(s) of radiation sensitivity and the ethical implications of current and potential knowledge that might be gained in the future. The report is concisely written, considers a large number of historical as well as recent studies, and features a ‘ bullet like ’ summary at the end of each chapter that captures the salient points.

  3. The Human Equation 

    E-print Network

    Natale, Michael J.

    This is a work in progress. It is Copyright ? Michael J. Natale. Star Trek characters are Copyright Paramount Pictures and are used without permission. Please don?t sue me. It is provided here for personal, non commercial use under a Creative... Commons Attribution-Non-Commercial-No Derivatives license. THE HUMAN EQUATION A work of Star Trek Fan Fiction by Michael J. Natale michael@seewhatsinmybrain.com CHAPTER ONE STARDATE: 3228.6 Near the Klingon Neutral Zone...

  4. Ecotoxicology of human pharmaceuticals.

    PubMed

    Fent, Karl; Weston, Anna A; Caminada, Daniel

    2006-02-10

    Low levels of human medicines (pharmaceuticals) have been detected in many countries in sewage treatment plant (STP) effluents, surface waters, seawaters, groundwater and some drinking waters. For some pharmaceuticals effects on aquatic organisms have been investigated in acute toxicity assays. The chronic toxicity and potential subtle effects are only marginally known, however. Here, we critically review the current knowledge about human pharmaceuticals in the environment and address several key questions. What kind of pharmaceuticals and what concentrations occur in the aquatic environment? What is the fate in surface water and in STP? What are the modes of action of these compounds in humans and are there similar targets in lower animals? What acute and chronic ecotoxicological effects may be elicited by pharmaceuticals and by mixtures? What are the effect concentrations and how do they relate to environmental levels? Our review shows that only very little is known about long-term effects of pharmaceuticals to aquatic organisms, in particular with respect to biological targets. For most human medicines analyzed, acute effects to aquatic organisms are unlikely, except for spills. For investigated pharmaceuticals chronic lowest observed effect concentrations (LOEC) in standard laboratory organisms are about two orders of magnitude higher than maximal concentrations in STP effluents. For diclofenac, the LOEC for fish toxicity was in the range of wastewater concentrations, whereas the LOEC of propranolol and fluoxetine for zooplankton and benthic organisms were near to maximal measured STP effluent concentrations. In surface water, concentrations are lower and so are the environmental risks. However, targeted ecotoxicological studies are lacking almost entirely and such investigations are needed focusing on subtle environmental effects. This will allow better and comprehensive risk assessments of pharmaceuticals in the future. PMID:16257063

  5. Human Body Odour Individuality

    Microsoft Academic Search

    Pavlina Lenochova; Jan Havlicek

    Humans produce temporarily stable, genetically mediated odour signatures and possess the ability to recognise, discriminate\\u000a and identify other people through the sense of smell. The capability of self, gender, kin and non-kin odour recognition plays\\u000a a role in social interactions. It seems that despite the stability of olfactory cues, the hedonic quality of body odour may\\u000a vary over time.

  6. The Human Oral Metagenome

    Microsoft Academic Search

    Peter Mullany; Philip Warburton; Elaine Allan

    \\u000a The human oral cavity is estimated to contain more than 750 bacterial species (Jenkinson and Lamont, 2005; Paster et al.,\\u000a 2006). Although this figure is controversial, the fact remains that up to half of the species in the oral microbiota cannot\\u000a yet be cultivated in the laboratory. Therefore, metagenomics is a powerful way of accessing these unculturable bacteria in\\u000a order

  7. NASA Human Spaceflight

    NSDL National Science Digital Library

    2007-12-12

    This site provides information on the International Space Station, space shuttle missions, and future human missions to Mars; current NASA news, NASA TV schedules, and information on spacecraft sighting opportunities; and descriptions of past NASA missions. There is a gallery of images, videos, and audio from NASA missions; outreach information on high school, college, teacher and faculty programs and resources; and a form to send questions to a space shuttle crew, space station crew, or mission control center.

  8. Polymerization into Human Hair

    Microsoft Academic Search

    CLARENCE ROBBINS; RICHARD CRAWFORD; D. W. McNEIL; JULIUS NACHTIGAL

    Synopsis-THIOGLYCOLIC ACID (TGA)-CUMENE HYDROPEROXIDE (CHP) and BISULFITE--CHP systems are described for po)ymerizing METHYL METHACRYLATE (MMA) in HUMAN HAIR. An ethanol-water solvent system was employed. Diffusion rate control appears to predominate over a variety of reaction conditions. The influence of reagent concentrations and so)vent effects on the reaction is also describe:). POLY- MERIZATION is shown to occur more rapidly into either

  9. A Human Telomeric Protein

    Microsoft Academic Search

    Laura Chong; Bas van Steensel; Dominique Broccoli; Hediye Erdjument-Bromage; John Hanish; Paul Tempst; Titia de Lange

    1995-01-01

    Telomeres are multifunctional element that shield chromosome ends from degradation and end-to-end fusions, prevent activation of DNA damage checkpoints, and modulate the maintenance of telomeric DNA by telomerase. A major protein component of human telomeres has been identified and cloned. This factor, TRF, contains one Myb-type DNA-binding repeat and an amino-terminal acidic domain. Immunofluorescent labeling shows that TRF specifically colocalizes

  10. Energy Use By Humans

    NSDL National Science Digital Library

    Arthur Few

    This module promotes an appreciation and understanding of energy and its behavior, how we use energy and what its appropriate uses are, some of the gross misuses of energy and how to learn from our mistakes so as to become better energy consumers, the value of fuels in the energy picture and the importance of economics and policy in influencing behavior, and how energy use by humans involves not just the energy itself, but the climate as well.

  11. The Human Vaginal Microbiome

    Microsoft Academic Search

    Brenda A. Wilson; Susan M. Thomas; Mengfei Ho

    \\u000a Humans live in association with abundant, complex, and dynamic microbial populations (the microbiome) that colonize many body\\u000a sites, including the vaginal tract. Interactions between the host and the vaginal microbiota greatly affect women’s health,\\u000a where they often serve a protective role in maintaining vaginal health. Disruption of the microbial composition can lead to\\u000a increased susceptibility to various urogenital diseases, including

  12. Human-powered Orrery

    NSDL National Science Digital Library

    2012-11-09

    In this space science activity, learners work together to create a human-powered orrery to model the movements of the four inner planets. Learners assist in setting up this moving model of the Solar System and take turns playing the roles of Mercury, Venus, Earth, and Mars. As learners observe the orrery in motion, they form conclusions about the orbital periods of the inner planets.

  13. Human Embryology Animations

    NSDL National Science Digital Library

    This collection features animations that illustrate a variety of the processes in the development of the human embryo. The collection was designed as a tool for medical students, but can serve as a review for other health-science practitioners and students. The animations are grouped by topic: cardiovascular embryology, development of the head and neck, gastrointestinal embryology, limb development, and urinary and reproductive embryology. They include written pre- and post-tests, and online assessment materials.

  14. Human papillomavirus vaccine update.

    PubMed

    Gilmer, Lisa S

    2015-03-01

    This article provides an overview of human papillomavirus (HPV) infection and the burden of HPV-related diseases, including cervical cancer, in the United States. The article presents an overview of HPV vaccination, including the efficacy and safety of the HPV vaccine, recommendations for vaccination in the adolescent population, as well as points to counter several of the common barriers to vaccination. This information is valuable to providers in their efforts to consistently and strongly recommend HPV vaccination. PMID:25634702

  15. The Human Body

    NSDL National Science Digital Library

    Ms. Colvin

    2010-11-04

    What are the major parts of the human body? First, you will need to open The Idea Wheel Graphic Organizer. You will record information about the major parts of the body, which include the head, neck, shoulders, arms, spine, and legs. I would like for you to record this information in each section of the idea wheel, as well as drawing pictures of each body part. ...

  16. Lipids in human milk

    Microsoft Academic Search

    Robert G. Jensen

    1999-01-01

    I have reviewed recent (March 1995–December 1997) papers on human milk lipids including many on fatty acid (FA) composition.\\u000a The effects of maternal diets on the profiles are apparent. However, more data on the composition of milk lipids are needed.\\u000a It is noteworthy that so few papers on milk FA composition have reported analyses using high-resolution gas-liquid chromatography\\u000a columns. Two

  17. Human Genetic Disorders

    Microsoft Academic Search

    Teresa M. Kruisselbrink; Noralane M. Lindor; Elyse B. Mitchell; Brittany C. Thomas; Cassandra K. Runke; Katrina E. Kotzer; Rajiv K. Pruthi; Devin Oglesbee; Elyse M. Grycki; Ralitza H. Gavrilova

    \\u000a The field of genetics continues to evolve at a rapid pace. The completion of the Human Genome project coupled with advancing\\u000a scientific techniques has led to the explosion of genetic information and testing capabilities ranging from rare genetic conditions\\u000a to common and sometimes preventable conditions. The Online Mendelian Inheritance in Man® (OMIM) found at http:\\/\\/www.ncbi.nlm.nih.gov\\/omim contains information on over 12,000

  18. Chemokines and human reproduction

    Microsoft Academic Search

    Juan A Garc??a-Velasco; Aydin Arici

    1999-01-01

    Objective: To review the available information regarding chemotactic cytokines and their possible implications in human reproduction.Design: A thorough literature and MEDLINE search was conducted to identify studies relating to the role of chemokines in ovulation, menstruation, implantation, cervical ripening and preterm labor, and endometriosis.Result(s): Chemokines mediate leukocyte traffic through their specific receptors in various tissues. Although four families have been

  19. Human Serum Paraoxonase

    Microsoft Academic Search

    Bharti Mackness; Paul N. Durrington; Michael I. Mackness

    1998-01-01

    1.Human serum paraoxonase (PON1) is a Ca2+-dependent 45-kDa glycoprotein that is associated with high density lipoprotein (HDL).2.PON1 hydrolyzes organophosphate (OP) insecticides and nerve gases and is responsible for determining the selective toxicity of these compounds in mammals.3.PON1 has two genetic polymorphisms giving rise to amino acid substitutions at positions 55 and 192. The position-192 polymorphism is the major determinant of

  20. The Human Equation

    E-print Network

    Natale, Michael J.

    This is a work in progress. It is Copyright ? Michael J. Natale. Star Trek characters are Copyright Paramount Pictures and are used without permission. Please don?t sue me. It is provided here for personal, non commercial use under a Creative... Commons Attribution-Non-Commercial-No Derivatives license. THE HUMAN EQUATION A work of Star Trek Fan Fiction by Michael J. Natale michael@seewhatsinmybrain.com CHAPTER ONE STARDATE: 3228.6 Near the Klingon Neutral Zone...

  1. Understanding Human Experience Henry Kautz

    E-print Network

    Kautz, Henry

    Understanding Human Experience Henry Kautz One of the earliest goals of research in artificial intelligence was to create systems that can interpret and understand day to day human experience. Early work on the goal of building systems that understand human experience. Each of the previous barriers is weakened

  2. NASA Space Human Factors Program

    NASA Technical Reports Server (NTRS)

    1992-01-01

    This booklet briefly and succinctly treats 23 topics of particular interest to the NASA Space Human Factors Program. Most articles are by different authors who are mainly NASA Johnson or NASA Ames personnel. Representative topics covered include mental workload and performance in space, light effects on Circadian rhythms, human sleep, human reasoning, microgravity effects and automation and crew performance.

  3. Genes, Environment, and Human Behavior.

    ERIC Educational Resources Information Center

    Bloom, Mark V.; Cutter, Mary Ann; Davidson, Ronald; Dougherty, Michael J.; Drexler, Edward; Gelernter, Joel; McCullough, Laurence B.; McInerney, Joseph D.; Murray, Jeffrey C.; Vogler, George P.; Zola, John

    This curriculum module explores genes, environment, and human behavior. This book provides materials to teach about the nature and methods of studying human behavior, raise some of the ethical and public policy dilemmas emerging from the Human Genome Project, and provide professional development for teachers. An extensive Teacher Background…

  4. Human Computation Luis von Ahn

    E-print Network

    Human Computation Luis von Ahn CMU-CS-05-193 December 7, 2005 School of Computer Science Carnegie, Peekaboom, Verbosity, Phetch, human computation, automated Turing tests, games with a purpose. #12 sophisticated computer programs. This thesis introduces a paradigm for utilizing human processing power to solve

  5. Human exposure to ultraviolet radiation

    SciTech Connect

    Passchier, W.F. (Health Council of the Netherlands, The Hague (NL)); Bosnjakovic, B.F.M. (Ministry of Housing, The Hague (NL))

    1987-01-01

    These proceedings contain over 50 selections. Some of the title are: Man and ultraviolet radiation; Effects of ultraviolet radiations on the human skin: emphasis on skin cancer; Human exposure to ultraviolet radiation: Quantitative modelling of skin cancer incidence; Human exposure to ultraviolet radiation: Data; and Share of erythema dose of solar radiation in high mountains.

  6. University of Windsor Human Rights

    E-print Network

    University of Windsor Human Rights Policy Approved by the Board of Governors June 12, 1997 #12;For further information or to obtain additional copies of this policy please contact the: HUMAN RIGHTS OFFICE: (519) 971-3673 #12;Human Rights Policy 1 PREAMBLE The University of Windsor is committed to providing

  7. HUMAN DEVELOPMENT Program of Study

    E-print Network

    Thomas, Andrew

    HUMAN DEVELOPMENT Program of Study Financial Aid Students Applying Correspondence The graduate program in Human Development is designed to provide advanced training, with special emphasis on child development and family relations. This program is designed for those interested in working in the human

  8. Humanities, Arts & Cultural Research and

    E-print Network

    Sokolowski, Marla

    Humanities, Arts & Cultural Research and Innovation Office of the Vice President, Research and Innovation www.research.utoronto.ca #12;U of T Humanities, Arts & Culture v 1.9 March 14, 2013 Report errors or omissions to andy.torr@utoronto.ca Page 2 of 71 HUMANITIES, ARTS & CULTURAL RESEARCH AND INNOVATION

  9. (Provisional syllabus) HUMANS AMONG ANIMALS

    E-print Network

    Goldberg, Bennett

    draw between humans and animals, or culture and nature, get redrawn ­ for psychological, political1 (Provisional syllabus) HUMANS AMONG ANIMALS KHC AN101 Honors College Freshman Seminar Prof of study is emerging in human-animal relations. Based partly on ancient questions and long-debated ideas

  10. Human Cognitive Neuropsychology PROGRAMME HANDBOOK

    E-print Network

    Edinburgh, University of

    MSc/Dip in Human Cognitive Neuropsychology PROGRAMME HANDBOOK 2011/2012 Psychology School Neuropsychology 2011/12 2 MSc/Dip in Human Cognitive Neuropsychology 2011-12 This booklet is a guide to the MSc/Dip programme in Human Cognitive Neuropsychology. It complements and augments the information in (a

  11. A human nonlinear cochlear filterbank

    Microsoft Academic Search

    Enrique A. Lopez-Poveda; Ray Meddis

    2001-01-01

    Some published cochlear filterbanks are nonlinear but are fitted to animal basilar membrane (BM) responses. Others, like the gammatone, are based on human psychophysical data, but are linear. In this article, a human nonlinear filterbank is constructed by adapting a computational model of animal BM physiology to simulate human BM nonlinearity as measured by psychophysical pulsation-threshold experiments. The approach is

  12. Automatic Detection of Human Nudes

    Microsoft Academic Search

    David A. Forsyth; Margaret M. Fleck

    1999-01-01

    This paper demonstrates an automatic system for telling whether there are human nudes present in an image. The system marks skin-like pixels using combined color and texture properties. These skin regions are then fed to a specialized grouper, which attempts to group a human figure using geometric constraints on human structure. If the grouper finds a sufficiently complex structure, the

  13. Human-Guided Tabu Search

    Microsoft Academic Search

    Gunnar W. Klau; Neal Lesh; Joe Marks; Michael Mitzenmacher

    2002-01-01

    We present a human-guidable and general tabu search algo- rithm. Our work expands on previous interactive optimization techniques that provide for substantial human control over as imple, exhaustive search algorithm. User experiments in four domains confirm that human guidance can improve the performance of tabu search and that people obtain superior results by guiding a tabu algorithm than by guiding

  14. Language Evolution and Human Development

    Microsoft Academic Search

    Brian MacWhinney

    Language is a unique hallmark of the human species. Although many species can communicate in limited ways about things that are physically present, only humans can construct a full narrative characterization of events occurring outside of the here and now. Humans are also unique in their ability to fashion tools such as arrow points, axes, traps, and clothing. By using

  15. Beyond Disciplinarity: Humanities and Supercomplexity

    ERIC Educational Resources Information Center

    Parker, Jan

    2008-01-01

    The "New Humanities" has called for new ways of engaging with Humanities texts; the European Science Foundation is just one major research funder to demand that the Humanities contribute to interdisciplinary collaborations. Meanwhile, traditionally trained disciplinary academics have resisted bringing traditional texts into interdisciplinary…

  16. HUMAN RESOURCES SIMON FRASER UNIVERSITY

    E-print Network

    HUMAN RESOURCES SIMON FRASER UNIVERSITY ADMINISTRATIVE & PROFESSIONAL JOB DESCRIPTION Position-Council Policy Statement: Ethical Conduct in Research Involving Humans (TCPS 2) are met. The Associate Director's Ethics Policy R20.01 and the Tri-Council Policy Statement: Ethical Conduct in Research Involving Humans

  17. MICHIGAN STATE UNIVERSITY HUMAN RESOURCES

    E-print Network

    MICHIGAN STATE UNIVERSITY HUMAN RESOURCES EDUCATIONAL ASSISTANCE PROGRAM APPLICATION (Also used Application, with department authorization, to Human Resources 30 days prior to Fees and Scholarships to the employee, within 15 days of Human Resource's receipt of the application, indicating if the course

  18. HUMAN RESOURCES SIMON FRASER UNIVERSITY

    E-print Network

    HUMAN RESOURCES SIMON FRASER UNIVERSITY ADMINISTRATIVE & PROFESSIONAL JOB DESCRIPTION Position and controls human resource deployment across the entire organization. Administers a web-based scheduling-line support staff. Works in collaborations with the Bookstore Retail Supervisor and SFU Human Resources

  19. Human Resources Personal Tax Increases

    E-print Network

    Lennard, William N.

    Human Resources Personal Tax Increases Retroactive to January 1, 2014 for Employees Earning over be done by logging in to My Human Resources. · Choose "Payroll and Compensation", then "Personal Tax are finished. If you have any questions about the tax deduction changes, please contact Human Resources at 519

  20. Onchocerca jakutensis Filariasis in Humans

    PubMed Central

    Koehsler, Martina; Soleiman, Afschin; Aspöck, Horst; Auer, Herbert

    2007-01-01

    We identified Onchocerca jakutensis as the causative agent of an unusual human filariasis in a patient with lupus erythematosus. To our knowledge, this is the first case of human infection with O. jakutensis and the first human case of zoonotic onchocercosis involving >1 worm. PMID:18217562