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1

Herpes simplex virus-mediated human hypoxanthine-guanine phosphoribosyltransferase gene transfer into neuronal cells  

SciTech Connect

The virtually complete deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) results in a devastating neurological disease, Lesch-Nyhan syndrome. Transfer of the HPRT gene into fibroblasts and lymphoblasts in vitro and into hematopoietic cells in vivo has been accomplished by other groups with retroviral-derived vectors. It appears to be necessary, however, to transfer the HPRT gene into neuronal cells to correct the neurological dysfunction of this disorder. The neurotropic virus herpes simplex virus type 1 has features that make it suitable for use as a vector to transfer the HPRT gene into neuronal tissue. This report describes the isolation of an HPRT-deficient rat neuroma cell line, designated B103-4C, and the construction of a recombinant herpes simplex virus type 1 that contained human HPRT cDNA. These recombinant viruses were used to infect B103-4C cells. Infected cells expressed HPRT activity which was human in origin.

Palella, T.D.; Silverman, L.J.; Schroll, C.T.; Homa, F.L.; Levine, M.; Kelley, W.N.

1988-01-01

2

Role of human hypoxanthine guanine phosphoribosyltransferase in activation of the antiviral agent T-705 (favipiravir).  

PubMed

6-Fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705) is a novel antiviral compound with broad activity against influenza virus and diverse RNA viruses. Its active metabolite, T-705-ribose-5'-triphosphate (T-705-RTP), is recognized by influenza virus RNA polymerase as a substrate competing with GTP, giving inhibition of viral RNA synthesis and lethal virus mutagenesis. Which enzymes perform the activation of T-705 is unknown. We here demonstrate that human hypoxanthine guanine phosphoribosyltransferase (HGPRT) converts T-705 into its ribose-5'-monophosphate (RMP) prior to formation of T-705-RTP. The anti-influenza virus activity of T-705 and T-1105 (3-hydroxy-2-pyrazinecarboxamide; the analog lacking the 6-fluoro atom) was lost in HGPRT-deficient Madin-Darby canine kidney cells. This HGPRT dependency was confirmed in human embryonic kidney 293T cells undergoing HGPRT-specific gene knockdown followed by influenza virus ribonucleoprotein reconstitution. Knockdown for adenine phosphoribosyltransferase (APRT) or nicotinamide phosphoribosyltransferase did not change the antiviral activity of T-705 and T-1105. Enzymatic assays showed that T-705 and T-1105 are poor substrates for human HGPRT having Km(app) values of 6.4 and 4.1 mM, respectively. Formation of the RMP metabolites by APRT was negligible, and so was the formation of the ribosylated metabolites by human purine nucleoside phosphorylase. Phosphoribosylation and antiviral activity of the 2-pyrazinecarboxamide derivatives was shown to require the presence of the 3-hydroxyl but not the 6-fluoro substituent. The crystal structure of T-705-RMP in complex with human HGPRT showed how this compound binds in the active site. Since conversion of T-705 by HGPRT appears to be inefficient, T-705-RMP prodrugs may be designed to increase the antiviral potency of this new antiviral agent. PMID:23907213

Naesens, Lieve; Guddat, Luke W; Keough, Dianne T; van Kuilenburg, André B P; Meijer, Judith; Vande Voorde, Johan; Balzarini, Jan

2013-10-01

3

Purinergic signaling in human pluripotent stem cells is regulated by the housekeeping gene encoding hypoxanthine guanine phosphoribosyltransferase.  

PubMed

Lesch-Nyhan disease (LND) is an X-linked genetic disorder caused by mutations of the hypoxanthine guanine phosphoribosyltransferase (HPRT) purine biosynthesis gene and characterized by aberrant purine metabolism, deficient basal ganglia dopamine levels, dystonia, and severe neurobehavioral manifestations, including compulsive self-injurious behavior. Although available evidence has identified important roles for purinergic signaling in brain development, the mechanisms linking HPRT deficiency, purinergic pathways, and neural dysfunction of LND are poorly understood. In these studies aimed at characterizing purinergic signaling in HPRT deficiency, we used a lentivirus vector stably expressing an shRNA targeted to the HPRT gene to produce HPRT-deficient human CVB induced pluripotent stem cells and human HUES11 embryonic stem cells. Both CVB and HUES11 cells show >99% HPRT knockdown and demonstrate markedly decreased expression of the purinergic P2Y1 receptor mRNA. In CVB cells, P2Y1 mRNA and protein down-regulation by HPRT knockdown is refractory to activation by the P2Y1 receptor agonist ATP and shows aberrant purinergic signaling, as reflected by marked deficiency of the transcription factor pCREB and constitutive activation of the MAP kinases phospho-ERK1/2. Moreover, HPRT-knockdown CVB cells also demonstrate marked reduction of phosphorylated ?-catenin. These results indicate that the housekeeping gene HPRT regulates purinergic signaling in pluripotent human stem cells, and that this regulation occurs at least partly through aberrant P2Y1-mediated expression and signaling. We propose that such mechanisms may play a role in the neuropathology of HPRT-deficiency LND and may point to potential molecular targets for modulation of this intractable neurological phenotype. PMID:22331909

Mastrangelo, Lina; Kim, Ji-Eun; Miyanohara, Atsushi; Kang, Tae Hyuk; Friedmann, Theodore

2012-02-28

4

Acyclic phosph(on)ate inhibitors of Plasmodium falciparum hypoxanthine-guanine-xanthine phosphoribosyltransferase  

PubMed Central

The pathogenic protozoa responsible for malaria lack enzymes for the de novo synthesis of purines and rely on purine salvage from the host. In Plasmodium falciparum (Pf), hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT) converts hypoxanthine to inosine monophosphate and is essential for purine salvage making the enzyme an anti-malarial drug target. We have synthesized a number of simple acyclic aza-C- nucleosides and shown that some are potent inhibitors of Pf HGXPRT while showing excellent selectivity for the Pf versus the human enzyme. PMID:23810424

Clinch, Keith; Crump, Douglas R.; Evans, Gary B.; Hazleton, Keith Z.; Mason, Jennifer M.; Schramm, Vern L.

2013-01-01

5

Hypoxanthine guanine phosphoribosyltransferase (HPRT) mutations in the Asian population.  

PubMed

Mutation of hypoxanthine guanine phosphoribosyltransferase (HPRT) gives rise to Lesch-Nyhan syndrome, which is characterized by hyperuricemia, severe motor disability, and self-injurious behavior, or HPRT-related gout (Kelley-Seegmiller syndrome). The marked heterogeneity of HPRT deficiency is well known, with more than 300 mutations at the HPRT gene locus having been reported (deletions, insertions, duplications, abnormal splicing, and point mutations at different sites of the coding region from exons 1 to 9). We have identified mutations in Asian families with patients manifesting different clinical phenotypes, including rare cases of female subjects, by analyzing all nine exons of the HPRT gene (HPRT1) from genomic DNA and reverse-transcribed mRNA using the polymerase chain reaction technique coupled with direct sequencing. We developed suitable methods to detect the mutations identified from respective families with HPRT deficiency. Then, prenatal genetic diagnoses in HPRT-deficient families were carried out using both mRNA and genomic DNA from chorionic villi or amniotic fluid cells. As shown here in the heterogeneity of HPRT mutations, the spectrum of 70 mutations identified in the Asian population fits the four main conclusions that emerged previously from worldwide analysis. PMID:22132982

Yamada, Y; Wakamatsu, N; Taniguchi, A; Kaneko, K; Fujimori, S

2011-12-01

6

Expression of the Methanobacterium thermoautotrophicum hpt Gene, Encoding Hypoxanthine (Guanine) Phosphoribosyltransferase, in Escherichia coli  

PubMed Central

The hpt gene from the archaeon Methanobacterium thermoautotrophicum, encoding hypoxanthine (guanine) phosphoribosyltransferase, was cloned by functional complementation into Escherichia coli. The hpt-encoded amino acid sequence is most similar to adenine phosphoribosyltransferases, but the encoded enzyme has activity only with hypoxanthine and guanine. The synthesis of the recombinant enzyme is apparently limited by the presence of the rare arginine codons AGA and AGG and the rare isoleucine AUA codon on the hpt gene. The recombinant enzyme was purified to apparent homogeneity. PMID:10074097

Sauer, Jørgen; Nygaard, Per

1999-01-01

7

Molecular analysis of five independent Japanese mutant genes responsible for hypoxanthine guanine phosphoribosyltransferase (HPRT) deficiency  

Microsoft Academic Search

Five independent mutations in the hypoxanthine guanine phosphoribosyltransferase (HPRT) gene were identified in a partially HPRT deficient patient with gout and in four Lesch-Nyhan patients. Using the polymerase chain reaction (PCR) technique coupled with direct sequencing, the nucleotide sequences of the entire HPRT coding region amplified from the cDNA and also of each exon amplified form the genomic DNA were

Yasukazu Yamada; Haruko Goto; Kaoru Suzumori; Ritsuko Adachi; Nobuaki Ogasawara

1992-01-01

8

Crystal structures of free, IMP-, and GMP-bound Escherichia coli hypoxanthine phosphoribosyltransferase  

PubMed Central

Crystal structures have been determined for free Escherichia coli hypoxanthine phosphoribosyltransferase (HPRT) (2.9 ? resolution) and for the enzyme in complex with the reaction products, inosine 5`-monophosphate (IMP) and guanosine 5`-monophosphate (GMP) (2.8 ? resolution). Of the known 6-oxopurine phosphoribosyltransferase (PRTase) structures, E. coli HPRT is most similar in structure to that of Tritrichomonas foetus HGXPRT, with a rmsd for 150 C? atoms of 1.0 ?. Comparison of the free and product bound structures shows that the side chain of Phe156 and the polypeptide backbone in this vicinity move to bind IMP or GMP. A nonproline cis peptide bond, also found in some other 6-oxopurine PRTases, is observed between Leu46 and Arg47 in both the free and complexed structures. For catalysis to occur, the 6-oxopurine PRTases have a requirement for divalent metal ion, usually Mg2+ in vivo. In the free structure, a Mg2+ is coordinated to the side chains of Glu103 and Asp104. This interaction may be important for stabilization of the enzyme before catalysis. E. coli HPRT is unique among the known 6-oxopurine PRTases in that it exhibits a marked preference for hypoxanthine as substrate over both xanthine and guanine. The structures suggest that its substrate specificity is due to the modes of binding of the bases. In E. coli HPRT, the carbonyl oxygen of Asp163 would likely form a hydrogen bond with the 2-exocyclic nitrogen of guanine (in the HPRT-guanine-PRib-PP-Mg2+ complex). However, hypoxanthine does not have a 2-exocyclic atom and the HPRT-IMP structure suggests that hypoxanthine is likely to occupy a different position in the purine-binding pocket. PMID:12070315

Guddat, Luke W.; Vos, Siska; Martin, Jennifer L.; Keough, Dianne T.; de Jersey, John

2002-01-01

9

Hypoxanthine-guanine phosphoribosyltransferase deficiency in a patient with a Madrid II mutation.  

PubMed

The hypoxanthine-guanine phosphoribosyltransferase deficiency is an inborn error of purine metabolism, linked to the X chromosome. The clinical phenotypes associated with HPRT deficiency varied according to the level of enzyme deficiency, with a large spectrum of neurologic features like self-injurious behaviour in patients with complete deficiency. We report a 20-year-old man who had asymmetric polyarthritis, tophi, hyperuricemia, nephrolithiasis and mild neurologic symptoms with undetectable levels of HPRT activity in lysed erythrocytes. The genetic study identified the c.143G>A mutation in exon 3, GAA CGT (CTT>GAA CAT CTT (48arg>his). The presence of gouty arthropathy and chronic hyperuricemia in a young patient with neurological symptoms, suggests HPRT deficiency for which it is necessary its enzyme and molecular determination. PMID:22999896

Sapag, Ana; Frischling, Eduardo; Laborde, Hugo

2013-01-01

10

[Partial deficiency of hypoxanthine-guanine phosphoribosyltransferase presenting seizure and psychomotor retardation: a case report].  

PubMed

An 18-year-old man was admitted to our hospital because of convulsive seizure. He had psychomotor retardation and intellectual disability from childhood, and had been diagnosed with attention deficit-hyperactivity disorder when he was 12 years old. He showed mental deficit (Wechsler Adult Intelligence Scale-Revised: IQ 52) and tendon hyperreflexia without pathological reflexes, but no involuntary movements or self-injurious behavior. As he had hyperuricemia, we measured the activity of hypoxanthine-guanine phosphoribosyltransferase (HPRT) and adenine phosphoribosyltransferase (APRT) in erythrocytes. While HPRT activity had decreased to 57.4% of normal, APRT activity had increased to 140.5% of normal. Genetic analysis revealed a single-base substitution (c.179A>G) in the third exon of the HPRT gene, which resulted in a missense mutation (p.H60R) of the 60th amino acid. His mother was a heterozygous carrier of this mutation and presented partial deficiency (73.3%) of HPRT activity. Lesch-Nyhan disease is a neurogenetic disorder caused by complete deficiency of the enzyme HPRT. Variant forms of the disease caused by partial deficiency of HPRT do not show the typical clinical features, or show only mild neurological manifestations; these diseases are jointly referred to as HPRT-related neurological disease (HRND). The present case was unique in that the patient diagnosed as having HRND showed relatively higher HPRT residual activity in erythrocytes. PMID:25420563

Yoshimoto, Takeshi; Himeno, Takahiro; Takeshima, Shinichi; Neshige, Shuichiro; Yamada, Kenichiro; Yamada, Yasukazu; Kuriyama, Masaru

2014-01-01

11

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

PubMed

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, choreoathetosis and compulsive self-mutilation. The HPRT-encoding gene is located on the X chromosome in the region q26-q27 and consists of nine exons and eight introns totalling 57 kb. This gene is transcribed to produce an mRNA of 1.6 kb, which contains a protein encoding region of 654 nucleotides. With the advent of increasingly refined techniques of molecular biology, it has been possible to study the HPRT gene of individuals with a deficiency in HPRT activity to determine the genetic basis of the enzyme deficiency. Many different mutations throughout the coding region have been described, but in the absence of precise information on the three-dimensional structure of the HPRT protein, it remains difficult to determine any consistent correlation between the structure and function of the enzyme. PMID:1487231

Sculley, D G; Dawson, P A; Emmerson, B T; Gordon, R B

1992-11-01

12

Hypoxanthine guanine phosphoribosyltransferase deficiency: nucleotide substitution causing Lesch-Nyhan syndrome identified for the first time among Japanese  

Microsoft Academic Search

A previously undescribed nucleotide substitution at codon 51 (CGA to TGA) has been identified using the polymerase chain reaction technique in hypoxanthine guanine phosphoribosyltransferase (HPRT) cDNA; this is the first molecular evidence for a point mutation in a Japanese patient with Lesch-Nyhan syndrome. The present mutation is the 19th nucleotide substitution identified as a germ-line mutation at this locus and

Shin Fujimori; Naoyuki Kamatani; Yutaro Nishida; Nobuaki Ogasawara; Ieo Akaoka

1990-01-01

13

Hypoxanthine guanine phosphoribosyltransferase (HPRT) deficiencies: HPRT1 mutations in new Japanese families and PRPP concentration.  

PubMed

Mutation of hypoxanthine guanine phosphoribosyltransferase (HPRT) gives rise to Lesch-Nyhan syndrome, which is characterized by hyperuricemia, severe motor disability, and self-injurious behavior, or HPRT-related gout with hyperuricemia. Four mutations were detected in two Lesch-Nyhan families and two families with partial deficiency since our last report. A new mutation of G to TT (c.456delGinsTT) resulting in a frameshift (p.Q152Hfs*3) in exon 3 has been identified in one Lesch-Nyhan family. In the other Lesch-Nyhan family, a new point mutation in intron 7 (c.532+5G>T) causing splicing error (exon 7 excluded, p.L163Cfs*4) was detected. In the two partial deficiency cases with hyperuricemia, two missense mutations of p.D20V (c.59A>T) and p.H60R (c.179A>G) were found. An increase of erythrocyte PRPP concentration was observed in the respective phenotypes and seems to be correlated with disease severity. PMID:24940672

Yamada, Yasukazu; Nomura, Noriko; Yamada, Kenichiro; Kimura, Reiko; Fukushi, Daisuke; Wakamatsu, Nobuaki; Matsuda, Yasufumi; Yamauchi, Takahiro; Ueda, Takanori; Hasegawa, Hiroshi; Nakamura, Makiko; Ichida, Kimiyoshi; Kaneko, Kiyoko; Fujimori, Shin

2014-01-01

14

Hypoxanthine-guanine phosphoribosyltransferase deficiency: analysis of HPRT mutations by direct sequencing and allele-specific amplification.  

PubMed

The Lesch-Nyhan syndrome is a severe X chromosome-linked human disease caused by a virtual absence of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity. A partial deficiency in the activity of this enzyme can result in gouty arthritis. To determine the genetic basis for reduction or loss of enzyme activity, we have amplified and sequenced the coding region of HPRT cDNA from four patients: one with Lesch-Nyhan syndrome (HPRTPerth) and three with partial deficiencies of HPRT activity, which have been designated HPRTUrangan, HPRTSwan and HPRTToowong. In all four patients, the only mutation identified was a single base substitution in exons 2 or 3 of the coding region, which in each case predicts a single amino acid substitution in the translated protein. Each base change was confirmed by allele-specific amplification of the patient's genomic DNA. It is interesting to note that the mutation found for HPRTPerth is identical to that reported for HPRTFlint. It appears that the two mutations are de novo events. PMID:1937471

Sculley, D G; Dawson, P A; Beacham, I R; Emmerson, B T; Gordon, R B

1991-10-01

15

The housekeeping gene hypoxanthine guanine phosphoribosyltransferase (HPRT) regulates multiple developmental and metabolic pathways of murine embryonic stem cell neuronal differentiation.  

PubMed

The mechanisms by which mutations of the purinergic housekeeping gene hypoxanthine guanine phosphoribosyltransferase (HPRT) cause the severe neurodevelopmental Lesch Nyhan Disease (LND) are poorly understood. The best recognized neural consequences of HPRT deficiency are defective basal ganglia expression of the neurotransmitter dopamine (DA) and aberrant DA neuronal function. We have reported that HPRT deficiency leads to dysregulated expression of multiple DA-related developmental functions and cellular signaling defects in a variety of HPRT-deficient cells, including human induced pluripotent stem (iPS) cells. We now describe results of gene expression studies during neuronal differentiation of HPRT-deficient murine ESD3 embryonic stem cells and report that HPRT knockdown causes a marked switch from neuronal to glial gene expression and dysregulates expression of Sox2 and its regulator, genes vital for stem cell pluripotency and for the neuronal/glial cell fate decision. In addition, HPRT deficiency dysregulates many cellular functions controlling cell cycle and proliferation mechanisms, RNA metabolism, DNA replication and repair, replication stress, lysosome function, membrane trafficking, signaling pathway for platelet activation (SPPA) multiple neurotransmission systems and sphingolipid, sulfur and glycan metabolism. We propose that the neural aberrations of HPRT deficiency result from combinatorial effects of these multi-system metabolic errors. Since some of these aberrations are also found in forms of Alzheimer's and Huntington's disease, we predict that some of these systems defects play similar neuropathogenic roles in diverse neurodevelopmental and neurodegenerative diseases in common and may therefore provide new experimental opportunities for clarifying pathogenesis and for devising new potential therapeutic targets in developmental and genetic disease. PMID:24130677

Kang, Tae Hyuk; Park, Yongjin; Bader, Joel S; Friedmann, Theodore

2013-01-01

16

The Housekeeping Gene Hypoxanthine Guanine Phosphoribosyltransferase (HPRT) Regulates Multiple Developmental and Metabolic Pathways of Murine Embryonic Stem Cell Neuronal Differentiation  

PubMed Central

The mechanisms by which mutations of the purinergic housekeeping gene hypoxanthine guanine phosphoribosyltransferase (HPRT) cause the severe neurodevelopmental Lesch Nyhan Disease (LND) are poorly understood. The best recognized neural consequences of HPRT deficiency are defective basal ganglia expression of the neurotransmitter dopamine (DA) and aberrant DA neuronal function. We have reported that HPRT deficiency leads to dysregulated expression of multiple DA-related developmental functions and cellular signaling defects in a variety of HPRT-deficient cells, including human induced pluripotent stem (iPS) cells. We now describe results of gene expression studies during neuronal differentiation of HPRT-deficient murine ESD3 embryonic stem cells and report that HPRT knockdown causes a marked switch from neuronal to glial gene expression and dysregulates expression of Sox2 and its regulator, genes vital for stem cell pluripotency and for the neuronal/glial cell fate decision. In addition, HPRT deficiency dysregulates many cellular functions controlling cell cycle and proliferation mechanisms, RNA metabolism, DNA replication and repair, replication stress, lysosome function, membrane trafficking, signaling pathway for platelet activation (SPPA) multiple neurotransmission systems and sphingolipid, sulfur and glycan metabolism. We propose that the neural aberrations of HPRT deficiency result from combinatorial effects of these multi-system metabolic errors. Since some of these aberrations are also found in forms of Alzheimer's and Huntington's disease, we predict that some of these systems defects play similar neuropathogenic roles in diverse neurodevelopmental and neurodegenerative diseases in common and may therefore provide new experimental opportunities for clarifying pathogenesis and for devising new potential therapeutic targets in developmental and genetic disease. PMID:24130677

Bader, Joel S.; Friedmann, Theodore

2013-01-01

17

Elevated frequencies of hypoxanthine phosphoribosyltransferase lymphocyte mutants are detected in Russian liquidators 6 to 10 years after exposure to radiation from the Chernobyl nuclear power plant accident  

Microsoft Academic Search

This study was conducted to determine whether the frequency of hypoxanthine phosphoribosyltransferase (HPRT) deficient lymphocyte mutants would detect an effect of radiation exposure in a population of Russians who were exposed to low levels of radiation while working in 1986 and 1987 as liquidators cleaning up after the Chernobyl nuclear power reactor accident. The HPRT lymphocyte cloning assay was performed

Cynthia B Thomas; David O Nelson; Pavel Pleshanov; Irina Vorobstova; Ludmila Tureva; Ronald Jensen; Irene M Jones

1999-01-01

18

Structural and functional studies of the human phosphoribosyltransferase domain containing protein 1.  

PubMed

Human hypoxanthine-guanine phosphoribosyltransferase (HPRT) (EC 2.4.2.8) catalyzes the conversion of hypoxanthine and guanine to their respective nucleoside monophosphates. Human HPRT deficiency as a result of genetic mutations is linked to both Lesch-Nyhan disease and gout. In the present study, we have characterized phosphoribosyltransferase domain containing protein 1 (PRTFDC1), a human HPRT homolog of unknown function. The PRTFDC1 structure has been determined at 1.7 Å resolution with bound GMP. The overall structure and GMP binding mode are very similar to that observed for HPRT. Using a thermal-melt assay, a nucleotide metabolome library was screened against PRTFDC1 and revealed that hypoxanthine and guanine specifically interacted with the enzyme. It was subsequently confirmed that PRTFDC1 could convert these two bases into their corresponding nucleoside monophosphate. However, the catalytic efficiency (k(cat)/K(m)) of PRTFDC1 towards hypoxanthine and guanine was only 0.26% and 0.09%, respectively, of that of HPRT. This low activity could be explained by the fact that PRTFDC1 has a Gly in the position of the proposed catalytic Asp of HPRT. In PRTFDC1, a water molecule at the position of the aspartic acid side chain position in HPRT might be responsible for the low activity observed by acting as a weak base. The data obtained in the present study indicate that PRTFDC1 does not have a direct catalytic role in the nucleotide salvage pathway. PMID:21054786

Welin, Martin; Egeblad, Louise; Johansson, Andreas; Stenmark, Pål; Wang, Liya; Flodin, Susanne; Nyman, Tomas; Trésaugues, Lionel; Kotenyova, Tetyana; Johansson, Ida; Eriksson, Staffan; Eklund, Hans; Nordlund, Pär

2010-12-01

19

Phenotypic Variation Among Seven Members of One Family with Deficiency of Hypoxanthine-Guanine Phosphoribosyltransferase  

PubMed Central

We describe a family of seven boys affected by Lesch-Nyhan disease with various phenotypes. Further investigations revealed a mutation c.203T>C in the gene encoding HGprt of all members, with substitution of leucine to proline at residue 68 (p.Leu68Pro). Thus patients from this family display a wide variety of symptoms although sharing the same mutation. Mutant HGprt enzyme was prepared by site-directed mutagenesis and the kinetics of the enzyme revealed that the catalytic activity of the mutant was reduced, in association with marked reductions in the affinity towards phosphoribosylpyrophosphate (PRPP). Its Km for PRPP was increased 215-fold with hypoxanthine as substrate and 40-fold with guanine as substrate with associated reduced catalytic potential. Molecular modeling confirmed that the most prominent defect was the dramatically reduced affinity towards PRPP. Our studies suggest that the p.Leu68Pro mutation has a strong impact on PRPP binding and on stability of the active conformation. This suggests that factors other than HGprt activity per se may influence the phenotype of Lesch-Nyhan patients. PMID:24075303

Ceballos-Picot, Irène; Augé, Franck; Fu, Rong; Olivier-Bandini, Anne; Cahu, Julie; Chabrol, Brigitte; Aral, Bernard; de Martinville, Bérengère; Lecain, Jean-Paul; Jinnah, H. A.

2013-01-01

20

Phenotypic variation among seven members of one family with deficiency of hypoxanthine-guanine phosphoribosyltransferase.  

PubMed

We describe a family of seven boys affected by Lesch-Nyhan disease with various phenotypes. Further investigations revealed a mutation c.203T>C in the gene encoding HGprt of all members, with substitution of leucine to proline at residue 68 (p.Leu68Pro). Thus patients from this family display a wide variety of symptoms although sharing the same mutation. Mutant HGprt enzyme was prepared by site-directed mutagenesis and the kinetics of the enzyme revealed that the catalytic activity of the mutant was reduced, in association with marked reductions in the affinity towards phosphoribosylpyrophosphate (PRPP). Its Km for PRPP was increased 215-fold with hypoxanthine as substrate and 40-fold with guanine as substrate with associated reduced catalytic potential. Molecular modeling confirmed that the most prominent defect was the dramatically reduced affinity towards PRPP. Our studies suggest that the p.Leu68Pro mutation has a strong impact on PRPP binding and on stability of the active conformation. This suggests that factors other than HGprt activity per se may influence the phenotype of Lesch-Nyhan patients. PMID:24075303

Ceballos-Picot, Irène; Augé, Franck; Fu, Rong; Olivier-Bandini, Anne; Cahu, Julie; Chabrol, Brigitte; Aral, Bernard; de Martinville, Bérengère; Lecain, Jean-Paul; Jinnah, H A

2013-11-01

21

Altered Turnover of Hypoxanthine Phosphoribosyltransferase in Erythroid Cells of Mice Expressing Hprt a and Hprt b Alleles  

PubMed Central

We have previously shown that mice expressing Hprt a allele(s) have erythrocyte hypoxanthine phosphoribosyltransferase (HPRT) levels that are approximately 25-fold (Mus musculus castaneus) and 70-fold ( Mus spretus) higher than in mice that express the Hprt b allele (Mus musculus domesticus; C57BI/6J; C3H/HeHa), and that these differences in erythrocyte HPRT levels are due to differences in the turnover rates of the HPRT A and B proteins as reticulocytes mature to erythrocytes. We show here that: (1) the taxonomic subgroups of the genus Mus are essentially monomorphic for the occurrence of either the Hprt a or the Hprt b allele, with Hprt a being common in the aboriginal species (M. spretus, Mus hortulanus and Mus abbotti) and in several commensal species (Mus musculus musculus, M. m. castaneus, Mus musculus molossinus), while Hprt b is common in feral M. m. domesticus populations as well as in all inbred strains of mice tested; (2) in all these diverse Mus subgroups there is a strict association of Hprt a with high and Hprt b with low levels of erythrocyte HPRT; and, (3) the association between the occurrence of the Hprt a allele and elevated erythrocyte HPRT levels is retained following repeated backcrosses of wild-derived Hprt a allele(s) into the genetic background of inbred strains of mice with the Hprt b allele. Collectively, these observations indicate that the elevated and low levels of erythrocyte HPRT are specified by differences in the Hprt a and b structural genes. Since evidence indicates that Hprt a and b encode HPRT proteins which differ in primary structure, we infer that the structure of HPRT is an important factor in determining its sensitivity to turnover in mouse erythroid cells. Hprt a and b may provide a useful system of "normal" allelic gene products for identifying factors that participate in protein turnover during mouse reticulocyte maturation. PMID:3609725

Johnson, Gerald G.; Chapman, Verne M.

1987-01-01

22

Altered turnover of hypoxanthine phosphoribosyltransferase in erythroid cells of mice expressing Hprt a and Hprt b alleles.  

PubMed

We have previously shown that mice expressing Hprt a allele(s) have erythrocyte hypoxanthine phosphoribosyltransferase (HPRT) levels that are approximately 25-fold (Mus musculus castaneus) and 70-fold (Mus spretus) higher than in mice that express the Hprt b allele (Mus musculus domesticus; C57BI/6J; C3H/HeHa), and that these differences in erythrocyte HPRT levels are due to differences in the turnover rates of the HPRT A and B proteins as reticulocytes mature to erythrocytes. We show here that: the taxonomic subgroups of the genus Mus are essentially monomorphic for the occurrence of either the Hprt a or the Hprt b allele, with Hprt a being common in the aboriginal species (M. spretus, Mus hortulanus and Mus abbotti) and in several commensal species (Mus musculus musculus, M. m. castaneus, Mus musculus molossinus), while Hprt b is common in feral M. m. domesticus populations as well as in all inbred strains of mice tested; in all these diverse Mus subgroups there is a strict association of Hprt a with high and Hprt b with low levels of erythrocyte HPRT; and, the association between the occurrence of the Hprt a allele and elevated erythrocyte HPRT levels is retained following repeated backcrosses of wild-derived Hprt a allele(s) into the genetic background of inbred strains of mice with the Hprt b allele. Collectively, these observations indicate that the elevated and low levels of erythrocyte HPRT are specified by differences in the Hprt a and b structural genes.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3609725

Johnson, G G; Chapman, V M

1987-06-01

23

Crystal Structure of Toxoplasma gondii Hypoxanthine-Guanine Phosphoribosyltransferase with XMP, Pyrophosphate, and Two Mg 2+ Ions Bound:  Insights into the Catalytic Mechanism † , ‡  

Microsoft Academic Search

The crystal structure of the Toxoplasma gondiihypoxanthine-guanine phosphoribosyltransferase (HGPRT)-xanthosine 5'-monophosphate (XMP)-pyrophosphate-Mg2+ ternary complex has been determined at 1.60 Å resolution. This biproduct, post-transition state structure is of a T. gondii HGPRT mutant (Asp150Ala or D150A). The D150A mutant has reduced activity (kcat lower by 11-, 296-, and 8.6-fold for hypoxanthine, guanine, and xanthine, respectively) compared to wild-type T. gondii HGPRT.

Annie Héroux; E. Lucile White; Larry J. Ross; Richard L. Davis; David W. Borhani

1999-01-01

24

Molecular characterization of two deletion events involving Alu -sequences, one novel base substitution and two tentative hotspot mutations in the hypoxanthine phosphoribosyltransferase (HPRT) gene in five patients with Lesch-Nyhan syndrome  

Microsoft Academic Search

Mutations identified in the hypoxanthine phosphoribosyltransferase (HPRT) gene of patients with Lesch-Nyhan (LN) syndrome\\u000a are dominated by simple base substitutions. Few hotspot positions have been identified, and only three large genomic rearrangements\\u000a have been characterized at the molecular level. We have identified one novel mutation, two tentative hot spot mutations, and\\u000a two deletions by direct sequencing of HPRT cDNA or

T. Tvrdik; Suzanne Marcus; Sai-Mei Hou; Susann Fält; Peri Noori; Natalia Podlutskaja; Folker Hanefeld; Petter Strømme; Bo Lambert

1998-01-01

25

Hydrophilic-interaction liquid chromatography-tandem mass spectrometric determination of erythrocyte 5-phosphoribosyl 1-pyrophosphate in patients with hypoxanthine-guanine phosphoribosyltransferase deficiency.  

PubMed

Mutations in the gene encoding hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause Lesch-Nyhan disease (LND) and its variants (LNV). Due to the technical problems for measuring the HPRT activity in vitro, discordances between the residual HPRT activity and the clinical severity were found. 5-Phosphoribosyl 1-pyrophosphate (PRPP) is a substrate for HPRT. Since increased PRPP concentrations were observed in erythrocytes from patients with LND and LNV, we have turned our attention to erythrocyte PRPP as a biomarker for the phenotype classification. In the present work, a method for determination of PRPP concentration in erythrocyte was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) with multiple reaction monitoring (MRM). Packed erythrocyte samples were deproteinized by heating and the supernatants were injected into the LC-MS/MS system. All measurement results showed good precision with RSD <6%. PRPP concentrations of nine normal male subjects, four male patents with LND and six male patients with LNV were compared. The PRPP concentrations in erythrocyte from patients with LND were markedly increased compared with those from normal subjects, and those from patients with LNV were also increased but the degree was smaller than those with LND. The increase pattern of PRPP concentration in erythrocyte from patients with HPRT deficiency was consistent with the respective phenotypes and was correlated with the disease severity. PRPP concentration was suggested to give us supportive information for the diagnosis and the phenotype classification of LND and LNV. PMID:25482009

Hasegawa, Hiroshi; Shinohara, Yoshihiko; Nozaki, Sayako; Nakamura, Makiko; Oh, Koei; Namiki, Osamu; Suzuki, Kiyotaka; Nakahara, Akihiko; Miyazawa, Mari; Ishikawa, Ken; Himeno, Takahiro; Yoshida, Sayaka; Ueda, Takanori; Yamada, Yasukazu; Ichida, Kimiyoshi

2015-01-22

26

Transition State Analogues of Plasmodium falciparum and Human Orotate Phosphoribosyltransferases*  

PubMed Central

The survival and proliferation of Plasmodium falciparum parasites and human cancer cells require de novo pyrimidine synthesis to supply RNA and DNA precursors. Orotate phosphoribosyltransferase (OPRT) is an indispensible component in this metabolic pathway and is a target for antimalarials and antitumor drugs. P. falciparum (Pf) and Homo sapiens (Hs) OPRTs are characterized by highly dissociative transition states with ribocation character. On the basis of the geometrical and electrostatic features of the PfOPRT and HsOPRT transition states, analogues were designed, synthesized, and tested as inhibitors. Iminoribitol mimics of the ribocation transition state in linkage to pyrimidine mimics using methylene or ethylene linkers gave dissociation constants (Kd) as low as 80 nm. Inhibitors with pyrrolidine groups as ribocation mimics displayed slightly weaker binding affinities for OPRTs. Interestingly, p-nitrophenyl riboside 5?-phosphate bound to OPRTs with Kd values near 40 nm. Analogues designed with a C5-pyrimidine carbon–carbon bond to ribocation mimics gave Kd values in the range of 80–500 nm. Acyclic inhibitors with achiral serinol groups as the ribocation mimics also displayed nanomolar inhibition against OPRTs. In comparison with the nucleoside derivatives, inhibition constants of their corresponding 5?-phosphorylated transition state analogues are largely unchanged, an unusual property for a nucleotide-binding site. In silico docking of the best inhibitor into the HsOPRT active site supported an extensive hydrogen bond network associated with the tight binding affinity. These OPRT transition state analogues identify crucial components of potent inhibitors targeting OPRT enzymes. Despite their tight binding to the targets, the inhibitors did not kill cultured P. falciparum. PMID:24158442

Zhang, Yong; Evans, Gary B.; Clinch, Keith; Crump, Douglas R.; Harris, Lawrence D.; Fröhlich, Richard F. G.; Tyler, Peter C.; Hazleton, Keith Z.; Cassera, María B.; Schramm, Vern L.

2013-01-01

27

Transition States of Plasmodium falciparum and Human Orotate Phosphoribosyltransferases†  

PubMed Central

Orotate phosphoribosyltransferases (OPRT) catalyze the formation of orotidine 5?-monophosphate (OMP) from ?-D-phosphoribosylpyrophosphate (PRPP) and orotate, an essential step in the de novo biosynthesis of pyrimidines. Pyrimidine de novo biosynthesis is required in Plasmodium falciparum, thus OPRT of the parasite (PfOPRT) is a target for anti-malarial drugs. De novo biosynthesis of pyrimidines is also a feature of rapidly-proliferating cancer cells. Human OPRT (HsOPRT) is therefore a target for neoplastic and autoimmune diseases. One approach to the inhibition of OPRTs is through analogues that mimic the transition states of PfOPRT and HsOPRT. The transition state structures of these OPRTs were analyzed by kinetic isotope effects (KIEs), substrate specificity and computational chemistry. With phosphonoacetic acid (PA), an analogue of pyrophosphate, the intrinsic KIEs of [1?-14C], [1, 3-15N2], [3-15N], [1?-3H], [2?-3H], [4?-3H] and [5?-3H2] are 1.034, 1.028, 0.997, 1.261, 1.116, 0.974 and 1.013 for PfOPRT and 1.035, 1.025, 0.993, 1.199, 1.129, 0.962 and 1.019 for HsOPRT, respectively. Transition state structures of PfOPRT and HsOPRT were determined computationally by matching the calculated and intrinsic KIEs. The enzymes form late associative DN*AN‡ transition states with complete orotate loss and partially-associative nucleophile. The C1?-OPA distances are approximately 2.1 Å at these transition states. The modest [1?-14C] KIEs and large [1?-3H] KIEs are characteristic of DN*AN‡ transition states. The large [2?-3H] KIEs indicate a ribosyl 2?-C-endo conformation at the transition states. p-Nitrophenyl ?-Dribose 5?-phosphate is a poor substrate of PfOPRT and HsOPRT but is a nanomolar inhibitor, supporting a reaction coordinate with strong leaving group activation. PMID:19292447

Zhang, Yong; Luo, Minkui; Schramm, Vern L.

2009-01-01

28

Use of phytohaemagglutinin stimulated lymphocytes to study effects of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency on polynucleotide and protein synthesis in the Lesch-Nyhan syndrome.  

PubMed

The incorporation of [14C]thymidine and [14C]uridine into the nucleoprotein, and [14C]phenylalanine into the protein by phytohaemagglutinin (PHA) stimulated lymphocytes from a patient with the Lesch-Nyhan syndrome [hypoxanthine-guanine phosphoribosyl transferase (EC 2.4.2.8 HGPRT) deficiency] and controls, was studied over 72 hours of incubation, with and without azaserine to block de novo purine biosynthesis. No difference was observed between the values obtained for Lesch-Nyhan and control lymphocytes, when PHA-stimulated without added azaserine. The percentage reduction in the incorporation of precursors into nucleoprotein and protein after PHA stimulation in the presence of azaserine was more obvious in the lymphocytes of the patient with the Lesch-Nyhan syndrome than in the controls after the shorter incubation periods at the lower rates of synthesis. Blocking the de novo purine biosynthetic pathway, in control PHA stimulated lymphocytes, inhibited transformation, whereas loss of the purine salvage enzyme HGPRT did not have this effect. These results are compatible with the view that the brain and bone-marrow damage that occur in the Lesch-Nyhan syndrome are the result of lack of HGPRT in tissues with little de novo purine biosynthetic capability. Other tissues with both pruine biosynthetic and salvage pathways are less vulnerable to the enzyme defect. Some possible mechanisms by which HGPRT deficiency could act are discussed. We suggest that inability to increase the supply of guanylic acid (GMP) in response to a mitotic stimulus may mediate the effect of HGPRT deficiency. PMID:933118

McKeran, R O; Watts, R W

1976-04-01

29

Regulation of purine utilization in bacteria. VI. Characterization of hypoxanthine and guanine uptake into isolated membrane vesicles from Salmonella typhimurium.  

PubMed Central

Uptake of hypoxanthine and guanine into isolated membrane vesicles of Salmonella typhimurium TR119 was stimulated by 5'-phosphoribosyl-1'-pyrophosphate (PRPP). For strain proAB47, a mutant that lacks guanine phosphoribosyltransferase, PRPP stimulated uptake of hypoxanthine into membrane vesicles. No PRPP-stimulated uptake of guanine was observed. For strain TR119, guanosine 5'-monophosphate and inosine 5'-monophosphate accumulated intravesicularly when guanine and hypoxanthine, respectively, were used with PRPP as transport substrates. For strain proAB47, IMP accumulated intravesicularly with hypoxanthine and PRPP as transport substrates. For strain TR119, hypoxanthine also accumulated when PRPP was absent. This free hypoxanthine uptake was completely inhibited by N-ethylmaleimide, but the PRPP-stimulated uptake of hypoxanthine was inhibited only 20% by N-ethylmaleimide. Hypoxanthine and guanine phosphoribosyltransferase activity paralleled uptake activity in both strains. But, when proAB47 vesicles were sonically treated to release the enzymes, a three- to sixfold activation of phosphoribosyltransferase molecules occurred. Since proAB47 vessicles lack the guanine phsophoribosyltransferase gene product and since hypoxanthine effectively competes out the phosphoribosylation of guanine by proAB47 vesicles, it was postulated that the hypoxanthine phosphoribosyltransferase gains specificity for both guanine and hypoxanthine when released from the membrane. A group translocation as the major mechanism for the uptake of guanine and hypoxanthine was proposed. PMID:770425

Jackman, L E; Hochstadt, J

1976-01-01

30

Recycling nicotinamide. The transition-state structure of human nicotinamide phosphoribosyltransferase  

PubMed Central

Human nicotinamide phosphoribosyltransferase (NAMPT) replenishes the NAD pool and controls the activities of sirtuins (SIRT), mono- and poly-(ADP-ribose) polymerases (PARP) and NAD nucleosidase (CD38). The nature of the enzymatic transition-state (TS) is central to understanding the function of NAMPT. We determined the TS structure for pyrophosphorolysis of nicotinamide mononucleotide (NMN) by kinetic isotope effects (KIEs). With the natural substrates, NMN and pyrophosphate (PPi), the intrinsic KIEs of [1?-14C], [1-15N], [1?-3H] and [2?-3H] are 1.047, 1.029, 1.154 and 1.093, respectively. A unique quantum computational approach was used for TS analysis that included structural elements of the catalytic site. Without constraints (e.g. imposed torsion angles), the theoretical and experimental data are in good agreement. The quantum-mechanical calculations incorporated a crucial catalytic site residue (D313), two magnesium atoms and coordinated water molecules. The transition state model predicts primary 14C, ?-secondary 3H, ?-secondary 3H and primary 15N KIE close to the experimental values. The analysis reveals significant ribocation character at the TS. The attacking PPi nucleophile is weakly interacting (rC-O = 2.60 Å) and the N-ribosidic C1?-N bond is highly elongated at the TS (rC-N = 2.35 Å), consistent with an ANDN mechanism. Together with the crystal structure of the NMN•PPi•Mg2•enzyme complex, the reaction coordinate is defined. The enzyme holds the nucleophile and leaving group in relatively fixed positions to create a reaction coordinate with C1?-anomeric migration from nicotinamide to the PPi. The transition state is reached by a 0.85 Å migration of C1?. PMID:23373462

Burgos, Emmanuel S.; Vetticatt, Mathew J.; Schramm, Vern L.

2013-01-01

31

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 ...

32

Regulation of hypoxanthine transport in Neurospora crassa  

E-print Network

the free bases are condensed with PRPP by membrane phosphoribosyltransferases resulting in intramem- branal accumulation of nucleoside monophosphates. Similarly, work with cultured human fibroblasts and cultured cell lines from patients with Lesch...

Sabina, Richard Lee

1976-01-01

33

Impairment of adenylyl cyclase 2 function and expression in hypoxanthine phosphoribosyltransferase-deficient rat B103 neuroblastoma cells as model for Lesch-Nyhan disease: BODIPY-forskolin as pharmacological tool.  

PubMed

Hypoxanthine phosphoribosyl transferase (HPRT) deficiency results in Lesch-Nyhan disease (LND). The link between the HPRT defect and the self-injurious behavior in LND is still unknown. HPRT-deficient rat B103 neuroblastoma cells serve as a model system for LND. In B103 cell membranes, HPRT deficiency is associated with a decrease of basal and guanosine triphosphate-stimulated adenylyl cyclase (AC) activity (Pinto and Seifert, J Neurochem 96:454-459, 2006). Since recombinant AC2 possesses a high basal activity, we tested the hypothesis that AC2 function and expression is impaired in HPRT deficiency. We examined AC regulation in B103 cell membranes, cAMP accumulation in intact B103 cells, AC isoform expression, and performed morphological studies. As most important pharmacological tool, we used 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene forskolin (BODIPY-FS) that inhibits recombinant AC2 but activates ACs 1 and 5 (Erdorf et al., Biochem Pharmacol 82:1673-1681, 2011). In B103 control membranes, BODIPY-FS reduced catalysis, but in HPRT(-) membranes, BODIPY-FS was rather stimulatory. 2'(3')-O-(N-methylanthraniloyl) (MANT)-nucleoside 5'-[?-thio]triphosphates inhibit recombinant ACs 1 and 5 more potently than AC2. In B103 control membranes, MANT-guanosine 5'-[?-thio]triphosphate inhibited catalysis in control membranes less potently than in HPRT(-) membranes. Quantitative real-time PCR revealed that in HPRT deficiency, AC2 was virtually absent. In contrast, AC5 was up-regulated. Forskolin (FS) and BODIPY-FS induced cell clustering and rounding and neurite extension in B103 cells. The effects of FS and BODIPY-FS were much more prominent in control than in HPRT(-) cells, indicative for a differentiation defect in HPRT deficiency. Neither FS nor BODIPY-FS significantly changed cAMP concentrations in intact B103 cells. Collectively, our data show that HPRT deficiency in B103 cells is associated with impaired AC2 function and expression and reduced sensitivity to differentiation induced by FS and BODIPY-FS. We discuss the pathophysiological implications of our data for LND. PMID:22552731

Kinast, Liz; von der Ohe, Juliane; Burhenne, Heike; Seifert, Roland

2012-07-01

34

Nicotinamide Phosphoribosyltransferase in Malignancy  

PubMed Central

Nicotinamide phosphoribosyltransferase (Nampt) catalyzes the rate-limiting step of nicotinamide adenine dinucleotide (NAD) synthesis. Both intracellular and extracellular Nampt (iNampt and eNampt) levels are increased in several human malignancies and some studies demonstrate increased iNampt in more aggressive/invasive tumors and in tumor metastases. Several different molecular targets have been identified that promote carcinogenesis following iNampt overexpression, including SirT1, CtBP, and PARP-1. Additionally, eNampt is elevated in several human cancers and is often associated with a higher tumor stage and worse prognoses. Here we review the roles of Nampt in malignancy, some of the known mechanisms by which it promotes carcinogenesis, and discuss the possibility of employing Nampt inhibitors in cancer treatment. PMID:24386506

Shackelford, Rodney E.; Mayhall, Kim; Maxwell, Nicole M.; Kandil, Emad

2013-01-01

35

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

Microsoft Academic Search

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

Rosa J Torres; Juan G Puig

2007-01-01

36

Hypoxanthine as a predictor of performance in highly trained athletes.  

PubMed

Purine metabolism reflects the exercise-induced muscle adaptations and training status. This study evaluated the utility of plasma hypoxanthine in the prediction of actual sport performance. We studied male athletes: 28 triathletes (21.4±2.9 years), 12 long-distance runners (23.2±1.9 years), 13 middle-distance runners (22.9±1.8 years) and 18 sprinters (22.0±2.7 years). Season-best race times were considered, achieved over standard triathlon, 5?000?m, 1?500?m and 100?m, respectively. Incremental treadmill test was administered to determine maximum and "threshold" oxygen uptake. Resting and post-exercise plasma concentrations of hypoxanthine, xanthine, uric acid and lactate were measured as well as resting erythrocyte hypoxanthine-guanine phosphoribosyltransferase activity. Simple and multiple regression analyses were used to identify significant contributors to the variance in performance. Hypoxanthine considered alone explained more variance in triathletes, long-distance runners, middle-distance runners and sprinters (r 2=0.81, 0.81, 0.88 and 0.78, respectively) than models based on aerobic capacity and lactate (R 2=0.51, 0.37, 0.59 and 0.31, respectively). Combining purine metabolites and cardiorespiratory variables resulted in the best prediction (R 2=0.86, 0.93, 0.93 and 0.91; r=0.93, 0.96, 0.96 and 0.95, respectively). In summary, hypoxanthine is a strong predictor of performance in highly trained athletes and its prediction ability is very high regardless of sport specialization, spanning the continuum from speed-power to endurance disciplines. PMID:23670363

Zieli?ski, J; Krasi?ska, B; Kusy, K

2013-12-01

37

Up-regulation of nicotinamide phosphoribosyltransferase and increase of NAD(+) levels by glucose restriction extend replicative lifespan of human fibroblast Hs68 cells.  

PubMed

Calorie restriction (CR) extends lifespan in a remarkable range of organisms. However, the mechanisms of CR related to the longevity effects are not fully elucidated to date. Using human fibroblast Hs68 (Hs68) cells cultured at a lower level of medium glucose (i.e., glucose restriction; GR) to mimic CR, we investigated the crucial role of nicotinamide phosphoribosyltransferase (Nampt), nicotinamide adenine dinucleotide (NAD(+)), and nicotinamide (NAM) in GR-extended replicative lifespan of Hs68 cells. We found that GR extended the lifespan of Hs68 cells, in parallel to significantly increased expression of Nampt, intracellular NAD(+) levels, and SIRT1 activities, and to significantly decreased NAM levels. The lifespan-extending effects of GR were profoundly diminished by FK866 (a noncompetitive inhibitor of Nampt) and blocked by sirtinol (a noncompetitive inhibitor of sirtuins). However, the steady-state intracellular NAM level (averaged 2.5 ?M) was much lower than the IC50 of NAM on human SIRT1 (about 50 ?M). All these results suggest that up-regulation of Nampt play an important role in GR-extended lifespan of Hs68 cells by increasing the intracellular NAD(+) levels followed by activating SIRT1 activity in Hs68 cells. In contrast, the role of NAM depletion is limited. PMID:25146190

Yang, Nae-Cherng; Song, Tuzz-Ying; Chang, Yan-Zin; Chen, Mei-Yau; Hu, Miao-Lin

2015-02-01

38

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

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

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

2000-01-01

39

Prospects for cellular mutational assays in human populations  

SciTech Connect

Practical, sensitive, and effective human cellular assays for detecting somatic and germinal mutations would have great value in environmental mutagenesis and carcinogenesis studies. Such assays would fill the void between human mutagenicity and the data that exist from short-term tests and from mutagenicity in other species. This paper discusses the following possible human cellular assays: (1) HPRT (hypoxanthine phosphoribosyltransferase) somatic cell mutation based on 6-thioguanine resistance; (2) hemoglobin somatic cell mutation assay; (3) glycophorin somatic cell mutation assay; and (4) LDH-X sperm cell mutation assay. 18 references.

Mendelsohn, M.L.

1984-06-29

40

Temporal order of replication of genes responsible for hypoxanthine phosphoribosyl transferase and Na/sup +//K/sup +/ ATPase in chemically transformed human fibroblasts  

SciTech Connect

The cytotoxic and mutagenic effects of a direct perturbation of DNA during various portions of the DNA synthetic period (S phase) of a chemically induced, transformed line (Hut-11A cells) derived from diploid human skin fibroblasts were examined. The cells were synchronized by a period of growth in low serum with a subsequent blockage of the cells at the G1/S boundary by hydroxyurea. This method resulted in over 90% synchrony, although approximately 20% of the cells were noncycling. Synchronized cells were treated for each of four 2-h periods during the S phase with 5-bromodeoxyuridine (BrdU) followed by irradiation with near-ultraviolet (UV). The BrdU-plus-irradiation treatment was cytotoxic and mutagenic, while treatment with BrdU alone or irradiation alone was neither cytotoxic nor mutagenic. The cytotoxicity was dependent upon the periods of S phase during which treatment was administered. The highest lethality was observed for treatment in early to middle S phase, particularly in the first 2 h of S phase, whereas scare lethality was observed in late S phase. The BrdU-plus-irradiation treatment induced ouabain- and 6-thioguanine-resistant mutants, while BrdU alone or irradiation alone was not mutagenic. Ouabain-resistant mutants were induced during early S phase by the BrdU-plus-irradiation treatment. 6-Thioguanine-resistant mutants, however, were induced during middle to late S phase. These results suggest that a certain region or regions in the DNA of Hut-11A cells, as designated by their specific temporal relationship in the S phase, may be more sensitive to the DNA perturbation by BrdU treatment plus near-UV irradiation for cell survival and that gene(s) responsible for Na/sup +//K/sup +/ ATPase is replicated during early S phase and gene(s) for hypoxanthine phosphoribosyl transferase is replicated during middle to late S phase.

Tsutsui, T.; Suzuki, N.; Elmore, E.; Maizumi, H.

1986-06-01

41

Age-dependent selection against hypoxanthine phosphoribosyl transferase-deficient cells in mouse haematopoiesis.  

PubMed

The basis of a previously observed difference in the level of contribution of hypoxanthine phosphoribosyltransferase-deficient cells between the haematopoietic and non-haematopoietic tissues of chimaeric and heterozygous mice has been clarified by studying two populations of female mice that differ only in that one is heterozygous for a null allele at the hprt locus and the other is wild type at this locus. Both populations are heterozygous for an electrophoretic variant allele at the X-linked Pgk-1 locus, so that X-chromosome inactivation generates cells expressing different isozymes of phosphoglycerate kinase which can be assayed to monitor cell selection. The results show that hypoxanthine phosphoribosyltransferase deficiency itself, rather than an effect of another X-linked gene, causes a reduced level of contribution to haematopoietic tissues. Further, the extent of the depletion increases significantly with age, and this effect is due to a progressive reduction in the level of contribution to haematopoietic tissues rather than to an increase in the level of contribution to non-haematopoietic tissues. PMID:8076522

Samuel, K; Clarke, A R; Ansell, J D; Hooper, M L

1993-07-01

42

Novel Hypoxanthine Guanine Phosphoribosyltransferase Gene Mutations in Saudi Arabian Hyperuricemia Patients  

PubMed Central

Over the past decade, a steady increase in the incidence of HPRT-related hyperuricemia (HRH) has been observed in Saudi Arabia. We examined all the nine exons of HPRT gene for mutations in ten biochemically confirmed hyperuricemia patients, including one female and three normal controls. In all, we identified 13 novel mutations in Saudi Arabian HPRT-related hyperuricemia patients manifesting different levels of uric acid. The Lys103Met alteration was highly recurrent and was observed in 50% of the cases, while Ala160Thr and Lys158Asn substitutions were found in two patients. Moreover, in 70% of the patients ?2 mutations were detected concurrently in the HPRT gene. Interestingly, one of the patients that harbored Lys103Met substitution along with two frameshift mutations at codons 85 and 160 resulting in shortened protein demonstrated unusually high serum uric acid level of 738??mol/L. Two of the seven point mutations that resulted in amino acid change (Lys103Met and Val160Gly) were predicted to be damaging by SIFT and Polyphen and were further analyzed for their protein stability and function by molecular dynamics simulation. The identified novel mutations in the HPRT gene may prove useful in the prenatal diagnosis and genetic counseling. PMID:25136576

Alanazi, Mohammed; Al-Arfaj, Abdulrahman Saud; Abduljaleel, Zainularifeen; Fahad Al-Arfaj, Hussein; Reddy Parine, Narasimha; Purusottapatnam Shaik, Jilani; Khan, Zahid; Ali Khan Pathan, Akbar

2014-01-01

43

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

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

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

2001-06-01

44

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

SciTech Connect

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.

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

2010-03-05

45

Functional significance of four successive glycine residues in the pyrophosphate binding loop of fungal 6-oxopurine phosphoribosyltransferases  

PubMed Central

Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is a key enzyme of the purine recycling pathway that catalyzes the conversion of 5-phospho-ribosyl-?-1-pyrophosphate and guanine or hypoxanthine to guanosine monophosphate (GMP) or inosine monophosphate (IMP), respectively, and pyrophosphate (PPi). We report the first crystal structure of a fungal 6-oxopurine phosphoribosyltransferase, the Saccharomyces cerevisiae HGPRT (Sc-HGPRT) in complex with GMP. The crystal structures of full length protein with (WT1) or without (WT2) sulfate that mimics the phosphate group in the PPi binding site were solved by molecular replacement using the structure of a truncated version (?7) solved beforehand by multiwavelength anomalous diffusion. Sc-HGPRT is a dimer and adopts the overall structure of class I phosphoribosyltransferases (PRTs) with a smaller hood domain and a short two-stranded parallel ?-sheet linking the N- to the C-terminal end. The catalytic loops in WT1 and WT2 are in an open form while in ?7, due to an inter-subunit disulfide bridge, the catalytic loop is in either an open or closed form. The closure is concomitant with a peptide plane flipping in the PPi binding loop. Moreover, owing the flexibility of a GGGG motif conserved in fungi, all the peptide bonds of the phosphate binding loop are in trans conformation whereas in nonfungal 6-oxopurine PRTs, one cis-peptide bond is required for phosphate binding. Mutations affecting the enzyme activity or the previously characterized feedback inhibition by GMP are located at the nucleotide binding site and the dimer interface. PMID:22610485

Moynié, Lucile; Giraud, Marie-France; Breton, Annick; Boissier, Fanny; Daignan-Fornier, Bertrand; Dautant, Alain

2012-01-01

46

Effect of hypoxanthine, antioxidants and allopurinol on cholinesterase activities in rats.  

PubMed

In the present study, we investigate the in vitro effect of hypoxanthine on acetylcholinesterase and butyrylcholinesterase activities in the hippocampus, striatum, cerebral cortex and serum of 15-, 30- and 60-day-old rats. Furthermore, we also evaluated the influence of antioxidants, namely ?-tocopherol (trolox) and ascorbic acid, and allopurinol to investigate the possible participation of free radicals and uric acid in the effects elicited by hypoxanthine on these parameters. Acetylcholinesterase and butyrylcholinesterase activities were determined according to Ellman et al. (Biochem Pharmacol 7:88-95, 1961), with some modifications. Hypoxanthine (10.0 ?M), when added to the incubation medium, enhanced acetylcholinesterase activity in the hippocampus and striatum of 15- and 30-day-old rats and reduced butyrylcholinesterase activity in the serum of 60-day-old rats. The administration of allopurinol and/or antioxidants partially prevented the alterations caused by hypoxanthine in acetylcholinesterase and butyrylcholinesterase activities in the cerebrum and serum of rats. Data indicate that hypoxanthine alters cholinesterase activities, probably through free radicals and uric acid production since the alterations were prevented by the administration of allopurinol and antioxidants. It is presumed that the cholinesterase system may be associated, at least in part, with the neuronal dysfunction observed in patients affected by Lesch-Nyhan disease. In addition, although extrapolation of findings from animal experiments to humans is difficult, it is conceivable that these vitamins and allopurinol might serve as an adjuvant therapy to avoid progression of brain damage in patients affected by this disease. PMID:23400363

Wamser, Morgahna Nathalie; Leite, Eduardo Fernandes; Ferreira, Vinícius Vialle; Delwing-de Lima, Daniela; da Cruz, José Geraldo Pereira; Wyse, Angela T S; Delwing-Dal Magro, Débora

2013-09-01

47

Combined suicide gene therapy for human colon cancer cells using adenovirus-mediated transfer of Escherichia coli cytosine deaminase gene and Escherichia coli uracil phosphoribosyltransferase gene with 5-fluorocytosine  

Microsoft Academic Search

The virus-directed enzyme\\/prodrug system using the Escherichia coli cytosine deaminase (CD) gene and 5-fluorocytosine (5-FC) suffers from a sensitivity limitation in many tumor cells. The E. coli uracil phosphoribosyltransferase (UPRT), which is a pyrimidine salvage enzyme, directly converts 5-fluorouracil (5-FU) to 5-fluorouridine monophosphate at the first step of its activating pathway. To improve the antitumoral effect of the CD\\/5-FC system,

Fumikazu Koyama; Hidetomo Sawada; Tomoko Hirao; Hisao Fujii; Hirofumi Hamada; Hiroshige Nakano

2000-01-01

48

In vivo footprint analysis and genomic sequencing of the human hypoxanthine-phosphoribosyl transferase (HPRT) 5 prime region on the active and inactive X chromosome  

SciTech Connect

In female placental mammals, one of the two X chromosome in each somatic cell is randomly inactivated during female embryogenesis as a mechanism for dosage compensation. Once a given X chromosome is inactivated, all mitotic progeny maintain the same X chromosome in the inactive state. DNA-protein interactions and DNA methylation are hypothesized to maintain this allele-specific system of differential gene expression. Ligation-mediated polymerase chain reaction (LMPCR) in vivo footprinting and genomic sequencing were used to study DNA-protein interactions and DNA-methylation within the 5{prime} region of the X-linked human HPRT gene on the active and inactive X chromosomes. In vivo footprint analysis reveals at least one DNA-protein interaction specific to the active HPRT allele in human male fibroblast cells and hamster-human hybrid cells containing only the active human X chromosome. In the region examined, all CpG dinucleotides are methylated on the inactive HPRT allele and unmethylated on the active X allele in hamster-human hybrid cells carrying either the inactive or active human X chromosome, respectively. Thus, DNA-methylation may be mediating the differential binding of sequence-specific DNA-binding proteins to the active or inactive HPRT alleles.

Hornstra, I.K.; Yang, T.P. (Univ. of Florida, Gainesville (United States))

1991-03-11

49

Trypanosoma brucei adenine-phosphoribosyltransferases mediate adenine salvage and aminopurinol susceptibility but not adenine toxicity?  

PubMed Central

African trypanosomes, like all obligate parasitic protozoa, cannot synthesize purines de novo and import purines from their hosts to build nucleic acids. The purine salvage pathways of Trypanosoma brucei being redundant, none of the involved enzymes is likely to be essential. Nevertheless they can be of pharmacological interest due to their role in activation of purine nucleobase or nucleoside analogues, which only become toxic when converted to nucleotides. Aminopurine antimetabolites, in particular, are potent trypanocides and even adenine itself is toxic to trypanosomes at elevated concentrations. Here we report on the T. brucei adenine phosphoribosyltransferases TbAPRT1 and TbAPRT2, encoded by the two genes Tb927.7.1780 and Tb927.7.1790, located in tandem on chromosome seven. The duplication is syntenic in all available Trypanosoma genomes but not in Leishmania. While TbAPRT1 is cytosolic, TbAPRT2 possesses a glycosomal targeting signal and co-localizes with the glycosomal marker aldolase. Interestingly, the distribution of glycosomal targeting signals among trypanosomatid adenine phosphoribosyltransferases is not consistent with their phylogeny, indicating that the acquisition of adenine salvage to the glycosome happened after the radiation of Trypanosoma. Double null mutant T. brucei ?tbaprt1,2 exhibited no growth phenotype but no longer incorporated exogenous adenine into the nucleotide pool. This, however, did not reduce their sensitivity to adenine. The ?tbaprt1,2 trypanosomes were resistant to the adenine isomer aminopurinol, indicating that it is activated by phosphoribosyl transfer. Aminopurinol was about 1000-fold more toxic to bloodstream-form T. brucei than the corresponding hypoxanthine isomer allopurinol. Aminopurinol uptake was not dependent on the aminopurine permease P2 that has been implicated in drug resistance. PMID:24596669

Lüscher, Alexandra; Lamprea-Burgunder, Estelle; Graf, Fabrice E.; de Koning, Harry P.; Mäser, Pascal

2013-01-01

50

Genetic instability at the adenine phosphoribosyltransferase locus in mouse L cells  

SciTech Connect

Resistance to adenine analogs such as 2,6-diaminopurine occurs at a rate of --10/sup -3/ per cell generation in mouse L cells. This resistance is associated with a loss of detectable adenine phosphoribosyltransferase activity. Other genetic loci in L cells have the expected mutation frequency (--10/sup -6/). Transformation of L cell mutants with Chinese hamster ovary cell DNA results in transformants with adenine phosphoribosyltransferase activity characteristic of Chinese hamster ovary cells. No activation of the mouse gene occurs on hybridization with human fibroblasts. That this high frequency event is the result of mutation rather than an epigenetic event is supported by antigenic and reversion studies of the 2,6-diaminopurine-resistant clones. These results are consistent with either a mutational hot-spot, a locus specific mutator gene, or a site of integration of an insertion sequence.

Tischfield, J.A.; Trill, J.J.; Lee, Y.; Coy, K.; Taylor, M.W.

1982-03-01

51

Yeast artificial chromosomes spanning 8 megabases and 10-15 centimorgans of human cytogenetic band Xq26  

SciTech Connect

A successful test is reported to generate long range contiguous coverage of DNA from a human cytogenetic band in overlapping yeast artificial chromosomes (YACs). Seed YACs in band Xq26 were recovered from a targeted library of clones from Xq24-q28 with 14 probes, including probes for the hypoxanthine guanine phosphoribosyltransferase- and coagulation factor IX-encoding genes and nine probes used in linkage mapping. Neighboring YACs were then identified by 25 walking' steps with end-clones, and the content of 71 probes in cognate YACs was verified by further hybridization analyses. The resultant contig extends across 8 million base pairs, including most of band Xq26, with an order of markers consistent with linkage data. YAC-based mapping, thus, permits steps toward a fully integrated physical and genetic map and is probably adequate to sustain most of the human genome project.

Little, R.D.; Pilia, G.; Johnson, S.; Schlessinger, D. (Washington Univ., St. Louis, MO (United States)); D'Urso, M. (International Inst. of Genetics and Biophysics, Naples (Italy))

1992-01-01

52

Evaluation of the mutagenic effects of myosmine in human lymphocytes using the HPRT gene mutation assay.  

PubMed

The minor tobacco alkaloid myosmine is implicated in DNA damage through pyridyloxobutylation similar to the tobacco-specific nitrosamines (TSNA). In contrast to TSNA, occurrence of myosmine is not restricted to tobacco. Myosmine is genotoxic to human cells in the comet assay. In this study, the mutagenic effect of myosmine was evaluated using the cloning hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene mutation assay. Four hour exposure of isolated peripheral blood lymphocytes from 14 subjects homozygous for the Leu84 wild-type of the O6-methylguanine-DNA-methyltransferase (MGMT) gene to 1mM of myosmine increased mutant frequency from 0.73+/-0.58 x 10(-6) in control to 1.14+/-0.89 x 10(-6) lymphocytes (P<0.05). These new data further confirm the mutagenic effects of myosmine. PMID:19041922

Havla, J B; Hill, C E; Abdel-Rahman, S Z; Richter, E

2009-01-01

53

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...

54

Regulatory elements in the introns of the human HPRT gene are necessary for its expression in embryonic stem cells  

SciTech Connect

The authors have examined the expression of transfected human hypoxanthine phosphoribosyltransferase minigenes (HPRT) in mouse embryonic stem (ES) cells. cDNA constructs of this gene that have been successfully used in somatic cell lines failed to confer hypoxanthine/aminopterin/thymidine (HAT) resistance in ES cells. In contrast, constructs containing introns 1 and 2 from the HPRT gene produced a high frequency of HAT-resistant colonies. This observation allowed them to identify two sequences in these introns that influence expression of the HPRT gene in ES cells. One element, located in intron 2, is required for effective HPRT expression in thee cells; the other element, located in intron 1, acts as an enhancer of HPRT expression. Using this information, they have constructed an HPRT minigene that can be used for either positive or negative selection in ES cell experiments. This dual capability allows the design of in-out procedures to create subtle changes in target genes by homologous recombination with the aid of this selectable minigene.

Reid, L.H.; Smithies, O.; Koller, B.H. (Univ. of North Carolina, Chapel Hill (USA)); Gregg, R.G. (Univ. of Wisconsin, Madison (USA))

1990-06-01

55

The function of nicotinamide phosphoribosyltransferase in the heart.  

PubMed

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

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

2014-11-01

56

An amperometric hypoxanthine biosensor based on Au@FeNPs for determination of hypoxanthine in meat samples.  

PubMed

A xanthine oxidase (XOD) from buttermilk was immobilized covalently onto boronic acid functionalized gold coated iron nanoparticles (Au@FeNPs) electrodeposited on pencil graphite (PG) electrode, via the boroester linkages, between free hydroxyl groups of boronic acid, ?-COOH and -NH2 groups of enzyme. The surface functionalization of Fe/Au nanoparticles with boronic acid (Au@FeNPs) on pencil graphite (PG) electrode was characterized by Fourier transform infrared (FTIR), cyclic voltammetry (CV), scanning electron microscopy (SEM), atomic force microscopy (AFM) and Electrochemical impedance spectroscopy (EIS) before and after immobilization of XOD. The biosensor exhibited optimum response within 3s at pH 7.2 and 30 °C and linearity in the range, 0.05 ?M to 150 ?M for hypoxanthine with a detection limit of 0.05 ?M (S/N=3). Apparent Michaelis Menten constant (Km(app)) for hypoxanthine was 40 ?M and Imax 0.125 mA. The biosensor was employed to determine hypoxanthine in fish, chicken, pork, beef meat and lost 50% of its initial activity after its 200 uses over 100 days, when stored at 4 °C. PMID:24140402

Devi, Rooma; Yadav, Sujata; Nehra, Renuka; Pundir, C S

2013-11-01

57

Adenine phosphoribosyltransferase (APRT) deficiency: identification of a novel nonsense mutation  

PubMed Central

Background Adenine phosphoribosyltransferase deficiency (APRTD) is an under estimated genetic form of kidney stones and/or kidney failure, characterized by intratubular precipitation of 2,8-dihydroxyadenine crystals (2,8-DHA). Currently, five pathologic allelic variants have been identified as responsible of the complete inactivation of APRT protein. Case presentation In this study, we report a novel nonsense mutation of the APRT gene from a 47- year old Italian patient. The mutation, localized in the exon 5, leads to the replacement of a cytosine with a thymine (g.2098C?>?T), introducing a stop codon at amino acid position 147 (p.Gln147X). This early termination was deleterious for the enzyme structural and functional integrity, as demonstrated by the structure analysis and the activity assay of the mutant APRT protein. Conclusion These data revealed that the p.Gln147X mutation in APRT gene might be a new cause of APRT disease. PMID:24986359

2014-01-01

58

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

PubMed Central

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. Images Figure 2 PMID:8054268

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

1994-01-01

59

Duplication in the hypoxanthine phosphoribosyl-transferase gene caused by Alu-Alu recombination in a patient with Lesch Nyhan syndrome  

Microsoft Academic Search

We have determined the structure, at the nucleotide sequence level, of a duplication in the hprt gene in a patient with Lesch-Nyhan syndrome (LN). The duplication extends over exons 7 and 8 and approximately 1.8 kb of the surrounding hprt sequence. The duplication junction is localized within two Alu sequences and has apparently been generated by unequal homologous recombination. This

Suzanne Marcus; Dennis Hellgren; Bo Lambert; Sven Petter Fällström; Jan Wahlström

1993-01-01

60

Analysis of the structural integrity of YACs comprising human immunoglobulin genes in yeast and in embryonic stem cells  

SciTech Connect

With the goal of creating a strain of mice capable of producing human antibodies, we are cloning and reconstructing the human immunoglobulin germline repertoire in yeast artificial chromosomes (YACs). We describe the identification of YACs containing variable and constant region sequences from the human heavy chain (IgH) and kappa light chain (IgK) loci and the characterization of their integrity in yeast and in mouse embryonic stem (ES) cells. The IgH locus-derived YAC contains five variable (V{sub H}) genes, the major diversity (D) gene cluster, the joining (J{sub H}) genes, the intronic enhancer (E{sub H}), and the constant region genes, mu (C{mu}) and delta (C{delta}). Two IgK locus-derived YACs each contain three variable (V{kappa}) genes, the joining (J{kappa}) region, the intronic enhancer (E{kappa}), the constant gene (C{kappa}), and the kappa deleting element (kde). The IgH YAC was unstable in yeast, generating a variety of deletion derivatives, whereas both IgK YACs were stable. YACs encoding heavy chain and kappa light chain, retrofitted with the mammalian selectable marker, hypoxanthine phosphoribosyltransferase (HPRT), were each introduced into HPRT-deficient mouse ES cells. Analysis of YAC integrity in ES cell lines revealed that the majority of DNA inserts were integrated in substantially intact form. 78 refs., 7 figs.

Mendez, M.J.; Abderrahim, H.; Noguchi, M. [Cell Genesys, Inc., Foster City, CA (United States)] [and others] [Cell Genesys, Inc., Foster City, CA (United States); and others

1995-03-20

61

Novel mutations in the human HPRT gene.  

PubMed

Inherited mutation of a purine salvage enzyme, hypoxanthine guanine phosphoribosyltransferase (HPRT), gives rise to Lesch-Nyhan Syndrome (LNS) or HPRT-related gout. Here, we report five novel independent mutations in the coding region of the HPRT gene from five unrelated male patients manifesting different clinical phenotypes associated with LNS: exon 2: c.133A > G, p.45R > G; c.35A > C, p.12D > A; c.88delG; exon 7: c.530A > T, p.177D > V; and c.318 + 1G > C: IVS3 + 1G > C splice site mutation. PMID:21780909

Nguyen, Khue Vu; Naviaux, Robert K; Paik, Kacie K; Nyhan, William L

2011-06-01

62

Effects of hypoxanthine substitution on bleomycin-mediated DNA strand degradation in DNA-RNA hybrids.  

PubMed Central

We have reported on the differences in site-specific cleavage between DNA and DNA-RNA hybrids by various prototypic DNA cleavers (accompanying paper). In the case of bleomycin (BLM), degradation at 5'-GC-3'sites was suppressed relative to the same sequence in double-stranded DNA, while 5'-GT-3' damage remained constant. We now present results of our further investigation on the chemical and conformational factors that contribute to BLM-mediated DNA strand cleavage of DNA-RNA hybrids. Substitution of guanine by hypoxanthine on the RNA strand of hybrids resulted in a significant enhancement of 5'-GC-3' site damage on the DNA strand relative to double-stranded DNA, thus reversing the suppression noted at these sites. Additionally, 5'-AT-3' sites, which are damaged significantly more in the hybrid than in DNA, exhibit decreased product formation when hypoxanthine is present on the RNA strand of hybrids. However, when hypoxanthine is substituted for guanine on the DNA strand (a GC cleavage site becomes IC), 5'-IT-3' and 5'-IC-3' site cleavage is almost completely suppressed, whereas AT site cleavage is dramatically enhanced. The priority in metallobleomycin site-specific cleavage of hybrids changes with hypoxanthine substitution: the cleavage priority is AT > GT > GC in native hybrid; GC > GT > AT in hybrids substituted with hypoxanthine in the RNA strand; AT >> GT approximately GC in hybrids substituted with hypoxanthine in the DNA strand. The results of kinetic isotope effect studies on BLM cleavage are presented and, in most cases, the values are larger for the hypoxanthine-substituted hybrid. The results suggest that the 2-amino groups of guanine residues on both strands of the nucleic acid play an important role in modulation of the binding and cleavage specificity of BLM. PMID:9108170

Bansal, M; Stubbe, J; Kozarich, J W

1997-01-01

63

Molybdenum cofactor (chlorate-resistant) mutants of Klebsiella pneumoniae M5al can use hypoxanthine as the sole nitrogen source.  

PubMed Central

Selection for chlorate resistance yields mol (formerly chl) mutants with defects in molybdenum cofactor synthesis. Complementation and genetic mapping analyses indicated that the Klebsiella pneumoniae mol genes are functionally homologous to those of Escherichia coli and occupy analogous genetic map positions. Hypoxanthine utilization in other organisms requires molybdenum cofactor as a component of xanthine dehydrogenase, and thus most chlorate-resistant mutants cannot use hypoxanthine as a sole source of nitrogen. Surprisingly, the K. pneumoniae mol mutants and the mol+ parent grew equally well with hypoxanthine as the sole nitrogen source, suggesting that K. pneumoniae has a molybdenum cofactor-independent pathway for hypoxanthine utilization. PMID:1400180

Garzón, A; Li, J; Flores, A; Casadesus, J; Stewart, V

1992-01-01

64

HIV-1 TAT-mediated protein transduction of human HPRT into deficient cells.  

PubMed

Lesch-Nyhan disease (LND) is a severe and incurable X-linked genetic syndrome caused by the deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT), resulting in severe alterations of central nervous system, hyperuricemia and subsequent impaired renal functions. Therapeutic options consist in supportive care and treatments of complications, but the disease remains largely untreatable. Enzyme replacement of the malfunctioning cytosolic protein might represent a possible therapeutic approach for the LND treatment. Protein transduction domains, such as the TAT peptide derived from HIV TAT protein, have been used to transduce macromolecules into cells in vitro and in vivo. The present study was aimed to the generation of TAT peptide fused to human HPRT for cell transduction in enzyme deficient cells. Here we document the construction, expression and delivery of a functional HPRT enzyme into deficient cells by TAT transduction domain and by liposome mediated protein transfer. With this approach we demonstrate the correction of the enzymatic defect in HPRT deficient cells. Our data show for the first time the feasibility of the enzyme replacement therapy for the treatment of LND. PMID:24129187

Cattelan, Paola; Dolcetta, Diego; Hladnik, Uros; Fortunati, Elisabetta

2013-11-01

65

Nicotinamide phosphoribosyltransferase can affect metastatic activity and cell adhesive functions by regulating integrins in breast cancer.  

PubMed

NAD(+) metabolism is an essential regulator of cellular redox reactions, energy pathways, and a substrate provider for NAD(+) consuming enzymes. We recently demonstrated that enhancement of NAD(+)/NADH levels in breast cancer cells with impaired mitochondrial NADH dehydrogenase activity, through augmentation of complex I or by supplementing tumor cell nutrients with NAD(+) precursors, inhibits tumorigenicity and metastasis. To more fully understand how aberrantly low NAD(+) levels promote tumor cell dissemination, we here asked whether inhibition of NAD(+) salvage pathway activity by reduction in nicotinamide phosphoribosyltransferase (NAMPT) expression can impact metastasis and tumor cell adhesive functions. We show that knockdown of NAMPT, the enzyme catalyzing the rate-limiting step of the NAD(+) salvage pathway, enhances metastatic aggressiveness in human breast cancer cells and involves modulation of integrin expression and function. Reduction in NAMPT expression is associated with upregulation of select adhesion receptors, particularly ?v?3 and ?1 integrins, and results in increased breast cancer cell attachment to extracellular matrix proteins, a key function in tumor cell dissemination. Interestingly, NAMPT downregulation prompts expression of integrin ?v?3 in a high affinity conformation, known to promote tumor cell adhesive interactions during hematogenous metastasis. NAMPT has been selected as a therapeutic target for cancer therapy based on the essential functions of this enzyme in NAD(+) metabolism, cellular redox, DNA repair and energy pathways. Notably, our results indicate that incomplete inhibition of NAMPT, which impedes NAD(+) metabolism but does not kill a tumor cell can alter its phenotype to be more aggressive and metastatic. This phenomenon could promote cancer recurrence, even if NAMPT inhibition initially reduces tumor growth. PMID:25263164

Santidrian, Antonio F; LeBoeuf, Sarah E; Wold, Erik D; Ritland, Melissa; Forsyth, Jane S; Felding, Brunhilde H

2014-11-01

66

Identification of novel mutations in the human HPRT gene.  

PubMed

Inherited mutation of the purine salvage enzyme, hypoxanthine guanine phosphoribosyltransferase (HPRT) gives rise to Lesch-Nyhan syndrome (LNS) or Lesch-Nyhan variants (LNVs). We report three novel independent mutations in the coding region of HPRT gene: exon 3: c.141delA, p.D47fs53X; exon 5: c.400G>A, p.E134K; exon 7: c.499A>G, p.R167G from three LNS affected male patients. PMID:23473102

Nguyen, Khue Vu; Nyhan, William L

2013-01-01

67

Thirdhand smoke causes DNA damage in human cells.  

PubMed

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

Hang, Bo; Sarker, Altaf H; Havel, Christopher; Saha, Saikat; Hazra, Tapas K; Schick, Suzaynn; Jacob, Peyton; Rehan, Virender K; Chenna, Ahmed; Sharan, Divya; Sleiman, Mohamad; Destaillats, Hugo; Gundel, Lara A

2013-07-01

68

Thirdhand smoke causes DNA damage in human cells  

PubMed Central

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

Hang, Bo

2013-01-01

69

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

PubMed Central

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

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

2014-01-01

70

Interaction studies of E. coli uracil phosphoribosyltransferase with 5-fluorouracil for potent anti cancer activity  

Microsoft Academic Search

Uracil phosphoribosyltransferase (UPRT) enzyme has immense potential in prodrug-mediated cancer therapy. Molecular docking\\u000a and enzyme inhibition studies are important for understanding drug–protein interaction in modern drug design. Herein, we experimentally\\u000a determined the enzyme inhibition constant (K\\u000a i) of 5-fluorouracil (5FU)—a competitive inhibitor of uracil, on UPRT purified from Escherichia coli. In silico experiments were performed on X-ray crystallography structure of

Vinod Kumar Yata; Kausik Sen; Mattaparthi Venkata Satish Kumar; Siddhartha Sankar Ghosh

71

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

PubMed Central

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

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

72

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

PubMed

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

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

73

Mutagenesis in human cells with accelerated H and Fe ions  

NASA Technical Reports Server (NTRS)

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.

Kronenberg, Amy

1994-01-01

74

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

E-print Network

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. ...

Pang, Bo

75

Electrophoretic properties of hypoxanthine-guanine phosphoribosyl transferase in erythrocytes of subjects with Lesch-Nyhan syndrome  

Microsoft Academic Search

Hypoxanthine-guanine phosphoribosyl transferase (HGPRT; E.C. 2.4.2.8) has been studied in erythrocytes of patients with Lesch-Nyhan syndrome by polyacrylamide gel electrophoresis. The location of this enzyme in gel was determined by radiochemical assay. Inosine monophosphate (the reaction product of HGPRT with radioactive hypoxanthine and 5-phosphorylribose-1-pyrophosphate) was precipitated in the gel at the site of its formation with lanthanum chloride. The zone

Bohdan Bakay; William L. Nyhan

1972-01-01

76

Incomplete nucleoside transport deficiency with increased hypoxanthine transport capability in mutant T-lymphoblastoid cells.  

PubMed Central

From a mutagenized population of wild-type mouse (S49) T-lymphoma cells, a clone, 80-5D2, was isolated in a single step by virtue of its ability to survive in 80 nM 5-fluorouridine. Unlike previously isolated nucleoside transport-deficient cell lines (A. Cohen, B. Ullman, and D. W. Martin, Jr., J. Biol. Chem. 254:112-116, 1979), 80-5D2 cells were only slightly less sensitive to growth inhibition by a variety of cytotoxic nucleosides and were capable of proliferating in hypoxanthine-amethopterin-thymidine-containing medium. The molecular basis for the phenotype of 80-5D2 cells was incomplete deficiency in the ability of the mutant cells to translocate nucleosides across the plasma membrane. Interestingly, mutant cells were more capable than wild-type cells of transporting the nucleobase hypoxanthine. Residual transport of adenosine into 80-5D2 cells was just as sensitive to inhibition by nucleosides and more sensitive to inhibition by hypoxanthine than that in wild-type cells, indicating that the phenomena of ligand binding and translocation can be uncoupled genetically. The 80-5D2 cells lacked cell surface binding sites for the potent inhibitor of nucleoside transport p-nitrobenzylthioinosine (NBMPR) and, consequently, were largely resistant to the physiological effects of NBMPR. However, the altered transporter retained its sensitivity to dipyridamole, another inhibitor of nucleoside transport. The biochemical phenotype of the 80-5D2 cell line supports the hypothesis that the determinants that comprise the nucleoside carrier site, the hypoxanthine carrier site, the NBMPR binding site, and the dipyridamole binding site of the nucleoside transport function of mouse S49 cells are genetically distinguishable. PMID:3491289

Aronow, B; Hollingsworth, P; Patrick, J; Ullman, B

1986-01-01

77

Partial hypoxanthine-guanine phosphoribosyl transferase deficiency with full expression of the Lesch-Nyhan syndrome  

Microsoft Academic Search

A patient with the full clinical expression of the classical Lesch-Nyhan syndrome is presented with a residual hypoxanthine-guanine phosphoribosyl transferase (HGPRT) activity of 5–10% in erythrocyte lysate and about 30% in fibroblast lysate. The activities of other erythrocyte enzymes of purine metabolism were typical for a classical Lesch-Nyhan patient. The effects of allopurinol therapy on the excretion of urinary purine

Gert Rijksen; Gerard E. J. Staal; Margreet J. M. van der Vlist; Frits A. Beemer; Jaap Troost; Wolf Gutensohn; Jan P. R. M. van Laarhoven; Chris H. M. M. de Bruyn

1981-01-01

78

Age-related macular degeneration-associated variants at chromosome 10q26 do not significantly alter ARMS2 and HTRA1 transcript levels in the human retina  

PubMed Central

Purpose Multiple studies demonstrate a strong association between three variants at chromosome 10q26 – rs10490924, del443ins54, and rs11200638 – near the age-related maculopathy susceptibility 2 (ARMS2) and high-temperature requirement factor A1 (HTRA1) genes with susceptibility to age-related macular degeneration (AMD). In different reports, the del443ins54 and rs11200638 variants are suggested to affect ARMS2 mRNA stability and/or HTRA1 mRNA expression, respectively. The goal of this study is to examine whether these AMD-associated variants alter expression levels of ARMS2 and HTRA1 in human retina samples. Methods Genomic DNA and total RNA were obtained from 35 human retinas (three young controls, average age=32 years; twenty aged controls, average age=72 years; and twelve AMD retinas, average age=77 years) using standard procedures. As ARMS2 exhibits higher expression in the human placenta, we also included eighteen placenta samples in our analysis. Four polymorphisms – rs2736911, rs10490924, del443ins54, and rs11200638 – were genotyped by PCR followed by sequencing. Expression of ARMS2, HTRA1 and three endogenous control genes (rRNA [rRNA], hypoxanthine phosphoribosyltransferase 1 [HPRT1], and glyceraldehyde-3-phosphate dehydrogenase [GAPDH]) was measured by real-time quantitative RT–PCR using Taqman gene expression or SYBR Green assays. Results ARMS2 and HTRA1 mRNA levels did not show a significant difference in expression among the control (young and elderly) and AMD retinas. No association of del443ins54 and rs11200638 variants was detected with mRNA expression levels of ARMS2 or HTRA1 in the retina. Human placenta samples showed high variability in expression levels. Conclusions We did not find association between AMD susceptibility variants at 10q26 and steady-state expression levels of either ARMS2 or HTRA1 in the human retina. PMID:20664794

Kanda, Atsuhiro; Stambolian, Dwight; Chen, Wei; Curcio, Christine A.; Abecasis, Gonçalo R.

2010-01-01

79

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

PubMed Central

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

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

2006-01-01

80

Overlapping protein-binding sites within a negative regulatory element modulate the brain-preferential expression of the human HPRT gene  

SciTech Connect

The hypoxanthine phosphoribosyltransferase (HPRT) gene, whose deficiency in humans causes the Lesch-Nyhan syndrome, is constitutively expressed at low levels in all tissues but at higher levels in the brain, the significance and mechanism of which is unknown. Towards dissecting this molecular mechanism, we have previously identified a 182 bp element (hHPRT-NE) within the 5{prime}-flanking region of the human HPRT gene which is involved not only in conferring neuronal specificity but also in repressing gene expression in non-neuronal tissues. Here we report that this element interacts with different nuclear proteins, some of which are present specifically in neuronal cells (complex I) and others of which are present in cells showing constitutive expression of the gene (complex II). In addition, we found that complex I factors are expressed in human NT2/D1 cells following induction of neuronal differentiation by retinoic acid. This finding correlates with an increase of HPRT gene transcription following neuronal differentiation, as demonstrated by RT-PCR and RNAase protection assays. We also mapped the binding sites for both complexes to a 60 bp region which, when tested by transient transfections in cultured fibroblasts, functioned as a repressor element. Methylation interference footprinting revealed a minimal unique DNA motif as the binding site for nuclear proteins from both neuronal and non-neuronal sources. Moreover, UV-crosslinking experiments showed that both complexes are formed by the association of several distinct proteins. Strikingly, site-directed mutagenesis of the footprinted region indicated that different nucleotides are essential for the association of these two complexes. These data suggest that differential formation of DNA-protein complexes at this regulatory domain could be a major determinant in the brain-preferential expression of the human HPRT gene.

Rincon-Limas, D.E.; Amaya-Manzanares, E.; Nino-Rosales, M.L. [Baylor College of Medicine, Houston, TX (United States)] [and others

1994-09-01

81

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

NASA Astrophysics Data System (ADS)

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.

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

2009-03-01

82

In vivo mutations in human blood cells: Biomarkers for molecular epidemiology  

SciTech Connect

Mutations arising in vivo in recorder genes of human blood cells provide biomarkers for molecular epidemiology by serving as surrogates for cancer-causing genetic changes. Current markers include mutations of the glycophorin-A (GPA) or hemoglobin (Hb) genes, measured in red blood cells, or mutations of the hypoxanthine-guanine phosphoribosyltransferase (hprt) or HLA genes, measured in T-lymphocytes. Mean mutant frequencies (variant frequencies) for normal young adults are approximately: Hb (4 [times] 10[sup [minus]8]) < hprt (5 [times] 10[sup [minus]6]) = GPA (10 [times] 10[sup [minus]6]) < HLA (30 [times] 10[sup [minus]6]). Mutagen-exposed individuals show decided elevations. Molecular mutational spectra are also being defined. For the hprt marker system, about 15% of background mutations are gross structural alterations of the hprt gene (e.g., deletions); the remainder are point mutations (e.g., base substitutions or frameshifts). Ionizing radiations result in dose-related increases in total gene deletions. Large deletions may encompass several megabases as shown by co-deletions of linked markers. Possible hprt spectra for defining radiation and chemical exposures are being sought. In addition to their responsiveness to environmental mutagens/carcinogens, three additional findings suggest that the in vivo recorder mutations are relevant in vivo surrogates for cancer mutations. First, a large fraction of GPA and HLA mutations show exchanges due to homologous recombination, an important mutational event in cancer. Second, hprt mutations arise preferentially in dividing T-cells, which can accumulate additional mutations in the same clone, reminiscent of the multiple hits required in the evolution of malignancy. Finally, fetal hprt mutations frequently have characteristic deletions of hprt exons 2 and 3, which appear to be mediated by the VDJ recombinase that rearranges the T-cell receptor genes during thymic ontogeny. 60 refs., 3 tabs.

Albertini, R.J.; Branda, R.F.; O'Neill, J.P. (Univ. of Vermont, Burlington (United States)); Nicklas, J.A.; Fuscoe, J.C. (Environmental Health Research and Testing, Inc., Research Triangle Park, NC (United States)); Skopek, T.R. (Univ. of North Carolina, Chapel Hill (United States))

1993-03-01

83

Expression of Escherichia coli uracil phosphoribosyltransferase gene in murine colon carcinoma cells augments the antitumoral effect of 5-fluorouracil and induces protective immunity  

Microsoft Academic Search

Uracil phosphoribosyltransferase (UPRT) of Escherichia coli origin can convert 5-fluorouracil (5-FU), a chemotherapeutic agent widely used for solid tumors, to an active intermediate, 5-fluorouridine-5?-monophosphate, as mammalian orotate phosphoribosyltransferase does. To examine whether the E. coli UPRT gene expressed in tumor cells can confer increased sensitivity to 5-FU, we retrovirally transduced Colon 26 cells, a murine colon carcinoma cell line, with

Kiyoko Kawamura; Kentaro Tasaki; Hirofumi Hamada; Keizo Takenaga; Shigeru Sakiyama; Masastoshi Tagawa

2000-01-01

84

Isolation and characterization of 5-fluorouracil-resistant mutants of Chinese hamster ovary cells deficient in the activities of orotate phosphoribosyltransferase and orotidine 5?-monophosphate decarboxylase  

Microsoft Academic Search

A rapid, simple method for isolation of large numbers of Chinese hamster ovary cell (CHO-K1) mutants deficient in the final two enzymes of UMP biosynthesis, orotate phosphoribosyltransferase (EC 2.4.2. 10), and OMP decarboxylase (EC 4.1.1.23) is described. The method takes advantage of the fact that CHO-K1 cells require orotate phosphoribosyltransferase to activate the pyrimidine analog 5-fluorouracil to its active form;

David Patterson

1980-01-01

85

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

PubMed

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

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

2011-09-30

86

Gold(I)-Triphenylphosphine Complexes with Hypoxanthine-Derived Ligands: In Vitro Evaluations of Anticancer and Anti-Inflammatory Activities  

PubMed Central

A series of gold(I) complexes involving triphenylphosphine (PPh3) and one N-donor ligand derived from deprotonated mono- or disubstituted hypoxanthine (HLn) of the general composition [Au(Ln)(PPh3)] (1–9) is reported. The complexes were thoroughly characterized, including multinuclear high resolution NMR spectroscopy as well as single crystal X-ray analysis (for complexes 1 and 3). The complexes were screened for their in vitro cytotoxicity against human cancer cell lines MCF7 (breast carcinoma), HOS (osteosarcoma) and THP-1 (monocytic leukaemia), which identified the complexes 4–6 as the most promising representatives, who antiproliferative activity was further tested against A549 (lung adenocarcinoma), G-361 (melanoma), HeLa (cervical cancer), A2780 (ovarian carcinoma), A2780R (ovarian carcinoma resistant to cisplatin), 22Rv1 (prostate cancer) cell lines. Complexes 4–6 showed a significantly higher in vitro anticancer effect against the employed cancer cells, except for G-361, as compared with the commercially used anticancer drug cisplatin, with IC50 ? 1–30 µM. Anti-inflammatory activity was evaluated in vitro by the assessment of the ability of the complexes to modulate secretion of the pro-inflammatory cytokines, i.e. tumour necrosis factor-? (TNF-?) and interleukin-1? (IL-1?), in the lipopolysaccharide-activated macrophage-like THP-1 cell model. The results of this study identified the complexes as auspicious anti-inflammatory agents with similar or better activity as compared with the clinically applied gold-based antiarthritic drug Auranofin. In an effort to explore the possible mechanisms responsible for the biological effect, the products of interactions of selected complexes with sulfur-containing biomolecules (L-cysteine and reduced glutathione) were studied by means of the mass-spectrometry study. PMID:25226034

K?ikavová, Radka; Hošek, Jan; Van?o, Ján; Hutyra, Jakub; Dvo?ák, Zden?k; Trávní?ek, Zden?k

2014-01-01

87

Identification of Hypoxanthine and Phosphoenolpyruvic Acid as Serum Markers of Chemoradiotherapy Response in Locally Advanced Rectal Cancer  

PubMed Central

Purpose Patients show variable responses to chemoradiotherapy (CRT), which is generally administered before surgery for locally advanced rectal cancer (LARC). The aim of this study was to identify molecular markers predictive of CRT responses by analysis of low-mass ions (LMIs) in serum of LARC patients. Materials and Methods LMIs (< 1,000 m/z) in serum obtained before CRT from 73 LARC (cT3-4) patients were profiled using matrix-assisted laser desorption/ionization mass spectrometry. LMIs with higher weighting factors in discriminating CRT responses were selected using principal components analysis and discriminant analysis. Selected LMIs were identified using the Human Metabolome Database. The concentrations of identified LMIs were determined by colorimetric enzyme assay, and compared according to post-CRT pathological stage (ypStage) or Dworak’s tumor regression grade (TRG). Results The nine highest-ranking LMIs were selected. Among them, two LMIs with 137.08 and 169.04 m/z were identified as hypoxanthine (HX) and phosphoenolpyruvic acid (PEP), respectively. Higher HX concentration was observed in patients with ypStage 0-1 compared to ypStage 2-4 (p=0.034) or ypStage 3-4 (p=0.030); a similar difference was observed between TRG 4-3 and TRG 1 (p=0.035). HX > 16.0 ?M showed significant association with ypStage 0-1 or TRG 4-3 than ypStage 3-4 (p=0.009) or TRG 1 (p=0.024), respectively. In contrast, a significantly lower concentration of PEP was observed in TRG 4-3 compared with TRG 2-1 (p=0.012). Conclusion Findings of this study demonstrated that serum concentrations of HX and PEP, identified using LMI profiling, may be useful for predicting the CRT response of LARC patients before treatment. PMID:25143052

Kim, Kun; Yeo, Seung-Gu; Yoo, Byong Chul

2015-01-01

88

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

PubMed Central

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

Farias, Percio Augusto Mardini; Castro, Arnaldo Aguiar

2014-01-01

89

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

Microsoft Academic Search

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

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

1994-01-01

90

Purine nucleotide synthesis in lymphoblasts cultured from normal subjects and a patient with Lesch-Nyhan syndrome  

Microsoft Academic Search

Human lymphoblasts derived from normal and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficient individuals have been maintained in permanent tissue culture, and comparative studies of their purine metabolism have been undertaken. In agreement with previous observations in fibroblasts, the HGPRT-deficient lymphoblasts (less than 2% normal HGPRT activity) demonstrate threefold increases in the production of purines by the de novo pathway and four- to

Alexander W. Wood; Michael A. Becker; J. Edwin Seegmiller

1973-01-01

91

Electron ionization of the nucleobases adenine and hypoxanthine near the threshold: a combined experimental and theoretical study.  

PubMed

Electron ionization of the DNA nucleobase, adenine, and the tRNA nucleobase, hypoxanthine, was investigated near the threshold region (?5-20 eV) using a high-resolution hemispherical electron monochromator and a quadrupole mass spectrometer. Ion efficiency curves of the threshold regions and the corresponding appearance energies (AEs) are presented for the parent cations and the five most abundant fragment cations of each molecule. The experimental ionization energies (IEs) of adenine and hypoxanthine were determined to be 8.70 ± 0.3 eV and 8.88 ± 0.5 eV, respectively. Quantum chemical calculations (B3LYP/6-311+G(2d,p)) yielded a vertical IE of 8.08 eV and an adiabatic IE of 8.07 eV for adenine and a vertical IE of 8.51 eV and an adiabatic IE of 8.36 eV for hypoxanthine, and the lowest energy optimized structures of the fragment cations and their respective neutral species were calculated. The enthalpies of the possible reactions from the adenine and hypoxanthine cations were also obtained computationally, which assisted in determining the most likely electron ionization pathways leading to the major fragment cations. Our results suggest that the imidazole ring is more stable than the pyrimidine ring in several of the fragmentation reactions from both adenine and hypoxanthine. This electron ionization study contributes to the understanding of the biological effects of electrons on nucleobases and to the database of the electronic properties of biomolecules, which is necessary for modeling the damage of DNA in living cells that is induced by ionizing radiation. PMID:25327785

Dawley, M Michele; Tanzer, Katrin; Cantrell, William A; Plattner, Peter; Brinkmann, Nicole R; Scheier, Paul; Denifl, Stephan; Ptasi?ska, Sylwia

2014-12-01

92

Increase in hypoxanthine-guanine phosphoribosyl transferase gene mutations by exposure to electric field.  

PubMed

Previously, we reported that exposure to extremely low frequency magnetic field (400 mT) increased in hypoxanthine-guanine phosphoribosyl transferase (HPRT) gene mutations. However, it is unclear these mutations were induced by magnetic field (MF), electric field (EF), or both. To explore this question, a new exposure apparatus for EF was manufactured. We observed an increase in HPRT gene mutations in Chinese hamster ovary (CHO) cells after exposure to EF (10 V/m, 60 Hz) for 10 h. The mutant frequency by EF-exposure was an approximate 2-fold of that by sham-exposure. Our data suggest that the mutations induced by exposure of cells to the variable magnetic field at 400 mT may be, in part, due to the induced EF. PMID:11212867

Ding, G R; Wake, K; Taki, M; Miyakoshi, J

2001-01-19

93

Nicotinamide phosphoribosyltransferase (Nampt) affects the lineage fate determination of mesenchymal stem cells: a possible cause for reduced osteogenesis and increased adipogenesis in older individuals.  

PubMed

Human aging is associated with a progressive decline in bone mass and an accumulation of marrow fat. We found that osteoblast differentiation was reduced and adipocyte formation increased in bone marrow stromal cells derived from aged mice compared with young controls. The increased adipogenesis correlated with a relatively lower Sirt1 activity and a lower intracellular NAD(+) concentration. We suppose that these effects were caused by age-related reduction of nicotinamide phosphoribosyltransferase (Nampt), the enzyme catalyzing NAD resynthesis from nicotinamide (NAM). In support of this hypothesis, treatment with Nampt inhibitor FK866 increased adipocyte formation and reduced mineralization in primary cultured bone marrow stromal cells. In addition, knockdown of Nampt in the mouse mesenchymal cell line C3H10T1/2?cells resulted in decreased Sirt1 activity and enhanced adipogenesis. Interestingly, although Nampt deficiency resulted in both decreased intracellular NAD(+) and increased NAM, the cell differentiation could be controlled only by regulation of NAM. These results indicate that the lineage fate determination of mesenchymal stem cells (MSCs) is influenced by cell energy metabolism and points to a possible mechanism for the development of senile osteoporosis. Furthermore, we suggest that side effects on bone should be considered when evaluating the long-term safety of NAD-interfering pharmaceuticals. PMID:21812028

Li, Yan; He, Xu; Li, Yulin; He, Jiaxue; Anderstam, Björn; Andersson, Göran; Lindgren, Urban

2011-11-01

94

Increasing NAD Synthesis in Muscle via Nicotinamide Phosphoribosyltransferase Is Not Sufficient to Promote Oxidative Metabolism.  

PubMed

The NAD biosynthetic precursors nicotinamide mononucleotide and nicotinamide riboside are reported to confer resistance to metabolic defects induced by high fat feeding in part by promoting oxidative metabolism in skeletal muscle. Similar effects are obtained by germ line deletion of major NAD-consuming enzymes, suggesting that the bioavailability of NAD is limiting for maximal oxidative capacity. However, because of their systemic nature, the degree to which these interventions exert cell- or tissue-autonomous effects is unclear. Here, we report a tissue-specific approach to increase NAD biosynthesis only in muscle by overexpressing nicotinamide phosphoribosyltransferase, the rate-limiting enzyme in the salvage pathway that converts nicotinamide to NAD (mNAMPT mice). These mice display a ?50% increase in skeletal muscle NAD levels, comparable with the effects of dietary NAD precursors, exercise regimens, or loss of poly(ADP-ribose) polymerases yet surprisingly do not exhibit changes in muscle mitochondrial biogenesis or mitochondrial function and are equally susceptible to the metabolic consequences of high fat feeding. We further report that chronic elevation of muscle NAD in vivo does not perturb the NAD/NADH redox ratio. These studies reveal for the first time the metabolic effects of tissue-specific increases in NAD synthesis and suggest that critical sites of action for supplemental NAD precursors reside outside of the heart and skeletal muscle. PMID:25411251

Frederick, David W; Davis, James G; Dávila, Antonio; Agarwal, Beamon; Michan, Shaday; Puchowicz, Michelle A; Nakamaru-Ogiso, Eiko; Baur, Joseph A

2015-01-16

95

Extracellular nicotinamide phosphoribosyltransferase (NAMPT) promotes M2 macrophage polarization in chronic lymphocytic leukemia.  

PubMed

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in nicotinamide adenine dinucleotide biosynthesis. In the extracellular compartment, it exhibits cytokine-/adipokinelike properties, suggesting that it stands at the crossroad between metabolism and inflammation. Here we show that both intracellular and extracellular NAMPT levels are increased in cells and plasma of chronic lymphocytic leukemia (CLL) patients. The extracellular form (eNAMPT) is produced by CLL lymphocytes upon B-cell receptor, Toll-like receptor, and nuclear factor ?B (NF-?B) signaling pathway activation. eNAMPT is important for differentiation of resting monocytes, polarizing them toward tumor-supporting M2 macrophages. These cells express high levels of CD163, CD206, and indoleamine 2,3-dioxygenase and secrete immunosuppressive (interleukin [IL] 10, CC chemokine ligand 18) and tumor-promoting (IL-6, IL-8) cytokines. NAMPT-primed M2 macrophages activate extracellular-regulated kinase 1/2, signal transducer and activator of transcription 3, and NF-?B signaling; promote leukemic cell survival; and reduce T-cell responses. These effects are independent of the enzymatic activity of NAMPT, as inferred from the use of an enzymatically inactive mutant. Overall, these results reveal that eNAMPT is a critical element in the induction of an immunosuppressive and tumor-promoting microenvironment of CLL. PMID:25368373

Audrito, Valentina; Serra, Sara; Brusa, Davide; Mazzola, Francesca; Arruga, Francesca; Vaisitti, Tiziana; Coscia, Marta; Maffei, Rossana; Rossi, Davide; Wang, Tao; Inghirami, Giorgio; Rizzi, Menico; Gaidano, Gianluca; Garcia, Joe G N; Wolberger, Cynthia; Raffaelli, Nadia; Deaglio, Silvia

2015-01-01

96

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

Microsoft Academic Search

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).

M Czauderna; J Kowalczyk

1997-01-01

97

GENOMICS 13, 788-796 (19%) Molecular Structure and Genetic Stability of Human Hypoxanthine  

E-print Network

leukemia cell line, while the third was originally iden- tified in a Lesch-Nyhan patient. All three duplication of HPRT exons 2 and 3 and of 6.8 kb (HL60 duplications) or 13.7 kb (Lesch-Nyhan duplication in HPRT in- trons 1 and 3, while the Lesch-Nyhan duplication was generated by the nonhomologous insertion

Monnat, Ray

98

Plasma visfatin/nicotinamide phosphoribosyltransferase levels in hypertensive elderly - results from the PolSenior substudy.  

PubMed

Visfatin/nicotinamide phosphoribosyltransferase (NAMPT), is a 52 kDa adipokine with proinflammatory properties produced mostly by macrophages and adipocytes from visceral adipose tissue. It seems that visfatin/NAMPT plays a role in the pathogenesis of arterial hypertension. As this condition is frequently present in the elderly, the aim of the study was to assess the plasma visfatin/NAMPT levels in normotensive and hypertensive subjects from the Polish elderly population. Visfatin/NAMPT levels were measured by specific enzyme-linked immunosorbent assay method in plasma samples from 2789 elderly subjects (1338 females, 1451 males) without heart failure, the PolSenior study participants, in addition to previously estimated serum concentrations of insulin, glucose, creatinine, C-reactive protein, and interleukin-6. Homeostasis model assessment for insulin resistance was calculated and used as a marker of insulin resistance. In the study group, 591 subjects were normotensive, 449 had untreated hypertension, and 1749 had treated hypertension. Plasma visfatin/NAMPT levels were not related to the presence of hypertension or the use of antihypertensive drugs, including angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists. The regression analysis revealed that plasma visfatin/NAMPT concentration variability is increased in subjects with high-sensitivity C-reactive protein concentration above 3 mg/L and with homeostasis model assessment for insulin resistance ?2.5, and decreased in those aged over 80 years. Our study shows that the presence of hypertension is not associated with the plasma levels of visfatin/NAMPT in elderly subjects. Plasma visfatin/NAMPT concentrations positively correlate with inflammation and insulin resistance, and are decreased in the oldest. PMID:25537462

Kocelak, Piotr; Olszanecka-Glinianowicz, Magdalena; Owczarek, Aleksander; Bo?entowicz-Wikarek, Maria; Brzozowska, Aniceta; Mossakowska, Ma?gorzata; Zdrojewski, Tomasz; Grodzicki, Tomasz; Wi?cek, Andrzej; Chudek, Jerzy

2015-01-01

99

Formation and trapping of free radicals in irradiated purines: EPR and ENDOR of hypoxanthine derivatives studied as single crystals  

NASA Astrophysics Data System (ADS)

Four different derivatives of hypoxanthine (hypoxanthine-HCl·H 2O, Na+·Inosine-·2.5H 2O, sodium inosine monophosphate, and calcium inosine monophosphate) were irradiated in the form of single crystals with the objective of identifying the radical products. To do so, magnetic resonance methods (EPR, ENDOR experiments and EPR spectrum simulations) were used to study radical products in crystals following x-irradiation at ˜10 K without warming, and under conditions of controlled warming. Also, computational chemistry methods were used in combination with the experimental methods to assist in identifying the radical products. Immediately following irradiation at 10 K, at least three different radicals were observed for hypoxanthine·HCl·H2O. R5.1 was identified at the product of electron addition followed by protonation of the parent at N3. R5.2 was identified as the product of electron loss followed by deprotonation at N7, and R5.3 was tentatively identified as the product of electron gain followed by protonation at 06. On warming to room temperature, three new radicals were observed: R6.1 and R6.3 were the products of net H addition to C8 and C2 respectively, while R6.2 was the product of OH addition to C8. At least four different radical products of Na+·Inosine - were detected immediately after irradiation at 10 K. R7.1 was identified as the electron-loss product of the parent hypoxanthine base, and R7.2 was identified as the product of net H-abstraction from C5 ' of the sugar. R7.3 and R7.4 were tentatively identified as the products of net H-addition to 06 (probably via electron addition followed by protonation), and the (doubly-negative) product of electron-gain, respectively. R7.5, the C8-H addition radical, was the only product detected on warming sodium inosine crystals to room temperature. Because the ENDOR spectra from sodium IMP irradiated at 10K were complex, it was possible to identify only two radicals. R8.1 was identified as the purine base electron-abstraction product, and R8.2 was identified as the 06 hydrogen-addition product. ENDOR spectra could be obtained from calcium IMP only at a few orientations. Thus, all radical identifications in this system are based on EPR spectrum simulations using likely radical structures based on results from other hypoxanthine-based systems.

Tokdemir, Sibel

100

Virtual Screening of Combinatorial Libraries across a Gene Family: in Search of Inhibitors of Giardia lamblia Guanine Phosphoribosyltransferase  

PubMed Central

Parasitic protozoa lack the ability to synthesize purine nucleotides de novo, relying instead on purine salvage enzymes for their survival. Guanine phosphoribosyltransferase (GPRT) from the protozoan parasite Giardia lamblia is a potential target for rational antiparasitic drug design, based on the experimental evidence, which indicates the lack of interconversion between adenine and guanine nucleotide pools. The present study is a continuation of our efforts to use three-dimensional structures of parasitic phosphoribosyltransferases (PRTs) to design novel antiparasitic agents. Two micromolar phthalimide-based GPRT inhibitors were identified by screening the in-house phthalimide library. A combination of structure-based scaffold selection using virtual library screening across the PRT gene family and solid phase library synthesis led to identification of smaller (molecular weight, <300) ligands with moderate to low specificity for GPRT; the best inhibitors, GP3 and GP5, had Ki values in the 23 to 25 ?M range. These results represent significant progress toward the goal of designing potent inhibitors of purine salvage in Giardia parasites. As a second step in this process, altering the phthalimide moiety to optimize interactions in the guanine-binding pocket of GPRT is expected to lead to compounds with promising activity against G. lamblia PRT. PMID:11502531

Aronov, Alex M.; Munagala, Narsimha R.; Kuntz, Irwin D.; Wang, Ching C.

2001-01-01

101

Roles for cationic residues at the quinolinic acid binding site of quinolinate phosphoribosyltransferase.  

PubMed

Quinolinic acid phosphoribosyltransferase (QAPRTase, EC 2.4.2.19) forms nicotinate mononucleotide (NAMN) from quinolinic acid (QA) and 5-phosphoribosyl 1-pyrophosphate (PRPP). Previously determined crystal structures of QAPRTase.QA and QAPRTase.PA.PRPP complexes show positively charged residues (Arg118, Arg152, Arg175, Lys185, and His188) lining the QA binding site. To assess the roles of these residues in the Salmonella typhimurium QAPRTase reaction, they were individually mutated to alanine and the recombinant proteins overexpressed and purified from a recombineered Escherichia coli strain that lacks the QAPRTase gene. Gel filtration indicated that the mutations did not affect the dimeric aggregation state of the enzymes. Arg175 is critical for the QAPRTase reaction, and its mutation to alanine produced an inactive enzyme. The k(cat) values for R152A and K185A were reduced by 33-fold and 625-fold, and binding affinity of PRPP and QA to the enzymes decreased. R152A and K185A mutants displayed 116-fold and 83-fold increases in activity toward the normally inactive QA analogue, nicotinic acid (NA), indicating roles for these residues in defining the substrate specificity of QAPRTase. Moreover, K185A QAPRTase displayed a 300-fold higher k(cat)/K(m) for NA over the natural substrate QA. Pre-steady-state analysis of K185A with QA revealed a burst of nucleotide formation followed by a slower steady-state rate, unlike the linear kinetics of WT. Intriguingly, pre-steady-state analysis of K185A with NA produced a rapid but linear rate for NAMN formation. The result implies a critical role for Lys185 in the chemistry of the QAPRTase intermediate. Arg118 is an essential residue that reaches across the dimer interface. Mutation of Arg118 to alanine resulted in 5000-fold decrease in k(cat) value and a decrease in the binding affinity of QA and PRPP to R152A. Equimolar mixtures of R118A with inactive or virtually inactive mutants produced approximately 50% of the enzymatic activity of WT, establishing an interfacial role for Arg118 during catalysis. PMID:20047306

Bello, Zainab; Grubmeyer, Charles

2010-02-23

102

A highly sensitive and automated method for the determination of hypoxanthine based on lab-on-valve approach using Fe3O4/MWCNTs/?-CD modified electrode.  

PubMed

A Fe(3)O(4)/multiwall carbon nanotubes/?-cyclodextrin (Fe(3)O(4)/MWCNTs/?-CD) modified electrode, for highly sensitive and automated hypoxanthine measurements, was developed in a sequential injection lab-on-valve system. The electrochemical oxidation behavior of hypoxanthine was investigated in phosphate buffer solution by cyclic voltammetry and linear sweep voltammetry. The Fe(3)O(4)/MWCNTs/?-CD modified electrode exhibits preferably analytical characteristics in electrocatalytic activity towards the oxidation of hypoxanthine. Under optimized conditions, the log oxidation peak current intensity was proportional to log hypoxanthine concentration covering the range from 5.0×10(-8) to 1.0×10(-5) mol L(-1) with a correlation coefficient of 0.9965. A detection limit of 0.3×10(-8) mol L(-1) was achieved along with a sampling frequency of 20 h(-1). This hyphenated system offers some advantages in terms of rapidness, sensitivity and ease of manipulation. Its further applications were utilized for the determination of hypoxanthine in meat samples. PMID:22967631

Wang, Yang; Wang, Lu; Tian, Tian; Yao, Guojun; Hu, Xiaoya; Yang, Chun; Xu, Qin

2012-09-15

103

Perspectives on fast-neutron mutagenesis of human lymphoblastoid cells.  

PubMed

The effects of low-fluence exposures to (Pu, Be) neutrons (En = 4.2 MeV) have been studied in a sensitive human B-lymphoblastoid cell line, TK6. Mutations were scored for two genetic loci, hypoxanthine phosphoribosyltransferase (hgprt) and thymidine kinase (tk), as a function of dose and dose rate. For exposures limited to less than one cell cycle, the mutation frequency for the hgprt locus was 1.92 X 10(-7)/cGy. When exposures were protracted over multiple cell generations, mutation yields were increased to 6.07 X 10(-7)/cGy. Similar yields were obtained for the induction of tk-deficient mutants with a normal cell generation time (tk-ng) when exposures were carried out at very low dose rates over multiple cell generations. In the series of data presented here, the results obtained for short-duration neutron exposures are compared with data obtained for monoenergetic heavy charged particles of defined linear energy transfer (LET) produced at the BEVALAC accelerator at Lawrence Berkeley Laboratory. TK6 cells have been exposed to beams ranging in atomic number from 20Ne to 40Ar over an energy range from 330 to 670 MeV/amu. Mutation induction was evaluated for both loci for a subset of these beams. The results obtained with 20Ne ions of 425 MeV/amu (LET = 32 keV/microns) and 28Si ions of 670 MeV/amu (LET = 50 keV/microns) closely resemble the mutation yields obtained for brief exposures to (Pu, Be) neutrons. The nature of alterations in DNA structure induced within the tk locus of tk-ng mutants is reviewed for a series of neutron-induced mutants and a series of mutants induced by exposure to 40Ar ions (470 MeV/amu, LET = 95 keV/microns). The mutational spectra for these two types of mutants were similar and were dominated by allele loss mutations. Multilocus deletions inclusive of the c-erbA1 locus were common among tk-deficient mutants induced by these densely ionizing radiations. For the mutants induced by 40Ar ions, it is likely that the mutations were produced by the traversal of the chromosome by a single particle. PMID:1924755

Kronenberg, A

1991-10-01

104

Time-dependent density functional theory (TD-DFT) study of the excited state proton transfer in hypoxanthine  

Microsoft Academic Search

Theoretical investigations on the ground- and excited-state proton transfer in the isolated and monohydrated forms of hypoxanthine have been performed. Ground- and transition-state geometries were optimized at the Hartree-Fock (HF)\\/6-311++G(d,p) and B3LYP\\/6-311++G(d,p) levels. The geometries of tautomers including the transition states were also optimized in the lowest singlet pipi* excited state at the CIS\\/6-311++G(d,p) level. The time-dependent density function theory

M. K. Shukla; Jerzy Leszczynski

2005-01-01

105

Localization of the gene that codes for adenine phosphoribosyltransferase on the genetic map of chromosome 8 of mouse  

SciTech Connect

Polymorphism of electrophoretic mobility of adenine phosphoribosyltransferase (APRT) was found in Mus musculus bactrianus, a population of domestic mouse. The presence of intraspecies polymorphism allows localization of the gene that codes for this enzyme on the genetic map of the 8th chromosome. Two markers were utilized to map the Aprt gene: the plasmin esterase-1, which is coded by the gene Es-1 located at a distance of 26 morganids from the centromere; and the Robertsonian translocation Rb(8.17)1 Iem, which marks the centromere. Results of the linkage analysis showed the gene Aprt to be located on the genetic map of the 8th chromosome at a distance of 51 morganids from the centromere and 25 morganids distil of the gene Es-1. Also discussed in this work was the influence of emotional stress on the recombination process in the 8th chromosome.

Nesterova, T.B.; Borodin, P.M.; Zakiyan, S.M.

1988-11-01

106

Preferential repair and strand-specific repair of benzo[a]pyrene diol epoxide adducts in the HPRT gene of diploid human fibroblasts.  

PubMed Central

If excision repair-proficient human cells are allowed time for repair before onset of S phase, the premutagenic lesions formed by (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy- 7,8,9,10-tetrahydrobenzo[a]pyrene (benzo[a]pyrene diol epoxide, BPDE) are lost from the transcribed strand of the hypoxanthine (guanine) phosphoribosyltransferase (HPRT) gene faster than from the nontranscribed strand. No change in strand distribution is seen with repair-deficient cells. These results suggest strand-specific repair of BPDE-induced DNA damage in human cells. To test this, we measured the initial number of BPDE adducts formed in each strand of the actively transcribed HPRT gene and the rate of repair, using UvrABC excinuclease in conjunction with Southern hybridization and strand-specific probes. We also measured the rate of loss of BPDE adducts from the inactive 754 locus. The frequencies of adducts formed by exposure to BPDE (1.0 or 1.2 microM) in either strand of a 20-kilobase fragment that lies entirely within the transcription unit of the HPRT gene were similar; the frequency in the 14-kilobase 754 fragment was approximately 20% lower. The rates of repair in the two strands of the HPRT fragment differed significantly. Within 7 hr after treatment with 1.2 microM BPDE, 53% of the adducts had been removed from the transcribed strand, but only 26% from the nontranscribed strand; after 20 hr, these values were 87% and 58%, respectively. In contrast, only approximately 14% of the BPDE adducts were lost from the 754 locus in 20 hr, a value even lower than the rate of loss from the overall genome (i.e., 38%). These results demonstrate strand-specific and preferential repair of BPDE adducts in human cells. They suggest that the heterogeneous repair of BPDE adducts in the human genome cannot be accounted for merely by the greatly increased rate of the repair specific to the transcribed strand of the active genes, and they point to a role for the chromatin structure. Images PMID:1608950

Chen, R H; Maher, V M; Brouwer, J; van de Putte, P; McCormick, J J

1992-01-01

107

High-Frequency Structural Gene Deletion as the Basis for Functional Hemizygosity of the Adenine Phosphoribosyltransferase Locus in Chinese Hamster Ovary Cells  

Microsoft Academic Search

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

Gerald M. Adair; Raymond L. Stallings; Rodney S. Nairn; Michael J. Siciliano

1983-01-01

108

Human hybrid hybridoma  

Microsoft Academic Search

Hybrid hybridomas are obtained by fusion of two cells, each producing its own antibody. Several authors have reported the construction of murine hybrid hybridomas with the aim to obtain bispecific monoclonal antibodies. The authors have investigated, in a model system, the feasibility of constructing a human hybrid hybridoma. They fused two monoclonal cell lines: an ouabain-sensitive and azaserine\\/hypoxanthine-resistant Epstein-Barr virus-transformed

R. F. Tiebout; F. van Boxtel-Oosterhof; E. A. M. Stricker; W. P. Zeijlemaker

1987-01-01

109

HPRT-APRT-deficient mice are not a model for lesch-nyhan syndrome  

Microsoft Academic Search

Complete hypoxanthine-guanine phosphoribosyl- transferase (HPRT) deficiency in humans results in the Lesch-Nyhan syndrome which is characterized, among other features, by compulsive self-injurious behavior. HPRT-deficient mice generated using mouse embryonic stem cells exhibit none of the behavioral symptoms associated with the Lesch-Nyhan syn- drome. Administration of drugs that inhibit adenine phosphoribosyltransferase (APRT) in HPRT-deficient mice has produced the suggestion that deficiency

Sandra J. Engle; Daniel E. Womer; Philip M. Davies; Greg Boivin; Amrik Sahota; H. Anne Simmonds; Peter J. Stambrook; Jay A. Tischfield

1996-01-01

110

Beta-endorphin immunoreactivity in spinal fluid and hypoxanthine in vitreous humour related to brain stem gliosis in sudden infant death victims  

Microsoft Academic Search

Beta-endorphin may induce respiratory depression and bradycardia. Elevated levels of hypoxanthine (HX) in vitreous humour (VH) may possibly indicate hypoxia before death. Furthermore, gliosis in the brain stem may reflect a previous hypoxic\\/ischaemic injury in the brain. In the present study we relate beta-endorphin immunoreactivity (BENDI) in the CSF to the presence or absence of reactive astrocytosis in the nucleus

Hanne Storm; Ola D. Saugstad; Karl L. Reichelt; Torleiv O. Rognum; Kari Skullerud

1994-01-01

111

Lesch-Nyhan syndrome: Absence of the mutant enzyme in erythrocytes of a heterozygote for both normal and mutant hypoxanthine-guanine phosphoribosyl transferase  

Microsoft Academic Search

Subjects heterozygous for the Lesch-Nyhan syndrome with a deficiency of the X-linked gene for the enzyme hypoxanthine-guanine phosphoribosyl transferase (PRT) would be expected to have two populations of erythrocytes in roughly equal proportions—one type with the normal enzyme and the other type exhibiting the mutant form of the enzyme. In contrast to this prediction, previous studies utilizing an X-linked gene

John A. McDonald; William N. Kelley

1972-01-01

112

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

Microsoft Academic Search

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

M Czauderna; J Kowalczyk

2000-01-01

113

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

SciTech Connect

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.

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

114

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

PubMed Central

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

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

2014-01-01

115

Plasma visfatin/nicotinamide phosphoribosyltransferase (visfatin/NAMPT) concentration is not related to kidney function in elderly subjects.  

PubMed

Abstract Background: Studies assessing plasma visfatin/nicotinamide phosphoribosyltransferase (NAMPT) concentrations in chronic kidney disease with the ELISA method are restricted mainly to subjects with end-stage kidney disease. Therefore, little is known about to what extent glomerular filtration rate (GFR) affects the plasma levels of visfatin/NAMPT. The aim of this study was to assess the relations between circulating visfatin/NAMPT levels and estimated GFR (eGFR), independently of potential confounders such as inflammation, nutritional status, and insulin resistance in the elderly population. Methods: The analysis included 3023 elderly subjects (1076 with impaired kidney excretory function - eGFR <60 mL/min/1.73 m2) who were participants of the PolSenior study. Serum insulin, glucose, creatinine, C-reactive protein, interleukin-6, and plasma visfatin/NAMPT concentrations were measured by a highly specific ELISA method. Insulin resistance was assessed on the basis of homeostasis model assessment for insulin resistance, and kidney excretory function was assessed using the full MDRD formula. Results: Similar plasma visfatin/NAMPT levels were found in subjects with eGFR ?60 and <60 mL/min/1.73 m2 (0.96 ng/mL in both groups), and even in those subjects with eGFR 15-30 mL/min/1.73 m2 (0.83 ng/mL). Additionally, there was no association between plasma visfatin/NAMPT concentrations and eGFR values in models of regression analysis including confounding factors. Conclusions: The results of our study suggest that plasma visfatin/NAMPT levels are not affected by impaired kidney excretory function in elderly subjects. PMID:25274953

Kocelak, Piotr; Olszanecka-Glinianowicz, Magdalena; Owczarek, Aleksander; Bozentowicz-Wikarek, Maria; Brzozowska, Aniceta; Mossakowska, Malgorzata; Skalska, Anna; Wiecek, Andrzej; Chudek, Jerzy

2014-10-01

116

Lesch-Nyhan syndrome and its pathogenesis: Purine concentrations in plasma and urine with metabolite profiles in CSF  

Microsoft Academic Search

Summary Purine metabolism in the Lesch-Nyhan syndrome has been re-examined in 10 patients. Hypoxanthine and xanthine concentrations in plasma and CSF and urinary excretion have been studied, on and off allopurinol treatment, using high performance liquid chromatographic methods. Accumulation of the substrate, hypoxanthine, of the missing hypoxanthine guanine phosphoribosyltransferase (HPRT) enzyme, is more marked in urine and in CSF than

R. A. Harkness; G. M. McCreanor; R. W. E. Watts

1988-01-01

117

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

PubMed Central

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

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

1992-01-01

118

Studies on the energy metabolism of opossum (Didelphis virginiana) erythrocytes: V. Utilization of hypoxanthine for the synthesis of adenine and guanine nucleotides in vitro  

SciTech Connect

High pressure liquid radiochromatography was used to test the ability of opossum erythrocytes to incorporate tracer amounts of (G-{sup 3}H) hypoxanthine (Hy) into ({sup 3}H) labelled triphosphates of adenine and guanine. In the presence of supraphysiologic (30 mM) phosphate which is optimal for PRPP synthesis, both ATP and GTP are extensively labelled. When physiologic (1 mM) medium phosphate is used, red cells incubated under an atmosphere of nitrogen accumulate ({sup 3}H) ATP in a linear fashion suggesting ongoing PRPP synthesis in red cells whose hemoglobin is deoxygenated. In contrast, a lesser increase of labelled ATP is observed in cells incubated under oxygen, suggesting that conditions for purine nucleotide formation from ambient Hy are more favorable in the venous circulation.

Bethlenfalvay, N.C.; White, J.C.; Chadwick, E.; Lima, J.E. (Fitzsimons Army Medical Center, Aurora, CO (USA))

1990-06-01

119

ANALYSIS OF X-RAY INDUCED HPRT MUTATIONS IN CHO CELLS: INSERTION AND DELETIONS  

EPA Science Inventory

Molecular alterations were examined in the hypoxanthine guanine phosphoribosyltransferase (hprt) gene of 41 independent X-ray-induced thioguanine-resistant (TGR) Chinese hamster ovary (CHO) cell clones. Rapid screening of the clones by multiplex polymerase chain reaction (PCR) fo...

120

Increased Frequency of Specific Locus Mutation Following Human Cytomegalovirus Infection  

Microsoft Academic Search

The effect of human cytomegalovirus (HCMV) infection on the frequency of mutations at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus was studied in Chinese hamster lung V79 cells. When V79 cells were infected with HCMV (strain AD169) at multiplicities of 0.1 to 50 plaque forming units (PFU) per cell the presumptive mutation frequency, as determined by the number of 6-thioguanine-resistant (TGr)

Thomas Albrecht; Michael P. Fons; Cheng Z. Deng; Istvan Boldogh

1997-01-01

121

Human gene mapping using an X\\/autosome translocation  

Microsoft Academic Search

Human fibroblasts containing a translocation between the X chromosome and chromosome 15 were fused with the 6-thioguanine-resistant mouse cell line, IR. Resulting hybrids, selected in HAT medium, retained the X\\/15 chromosome. Hybrids which were counterselected in 6-thioguanine lost this chromosome. The X-linked markers glucose-6-phosphate dehydrogenase (G6PD), phosphoglycerate kinase (PGK), and hypoxanthine phosphoribosyl transferase (HPRT), and the non-X-linked markers pyruvate kinase

E. Solomon; M. Bobrow; P. N. Goodfellow; W. F. Bodmer; D. M. Swallow; S. Povey; B. Noël

1976-01-01

122

Human somatic mutation assays as biomarkers of carcinogenesis  

SciTech Connect

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.

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

123

Lesch-Nyhan syndrome presenting as acute renal failure secondary to obstructive uropathy  

Microsoft Academic Search

Lesch-Nyhan syndrome is a rare genetic disorder characterized by mental retardation, self-mutilation, choreoathetosis, and hyperuricemia. The disease is caused by a mutation in the hypoxanthine-guanine phosphoribosyltransferase gene and is transmitted as a sex-linked recessive disorder. Since hyperuricemia is the primary metabolic problem caused by a hypoxanthine-guanine phosphoribosyltransferase mutation, urologic evaluation and treatment is often necessary for children with this disease.

MuralikK Ankem; David B Glazier; Joseph G Barone

2000-01-01

124

Photosensitized oxidation of hypoxanthine and xanthine by aluminum phthalocyanine tetrasulfonate. Role of the alkylating quinone 2,5-dichloro-diaziridinyl-1,4-benzoquinone.  

PubMed

Photoirradiation of nitrogen-saturated aqueous solutions containing aluminum phthalocyanine tetrasulfonate (AlPcS4) at 675 nm in the presence of 2,5-dichloro-diaziridinyl-1,4-benzoquinone (AZDClQ) and hypoxanthine (HX) produces the oxidized HX derivatives, xanthine (X) and uric acid (UA). Concentrations of the AZDClQ semiquinone, X and UA increase at the expense of HX with an increase in irradiation time. Almost negligible decomposition of HX, as well as very low amounts of X, are detected if photolysis occurs under identical conditions but in the absence of AZDClQ. Addition of calf-thymus DNA produces quinone-DNA covalent adducts after photolysis of anaerobic samples containing quinone, DNA and AlPcS4, in the presence or absence of HX and at pH 5.5. However, larger amounts of quinone-DNA adducts are detected if HX is present. The results presented here could have applications in the photodynamic treatment of hypoxic tissues such as solid tumors, under conditions of high HX concentration, where Type-I pathways could be more important than singlet oxygen generation. PMID:18627517

Alegria, Antonio E; Inostroza, Yaritza; Kumar, Ajay

2008-01-01

125

Photosensitized Oxidation of Hypoxanthine and Xanthine by Aluminum Phthalocyanine Tetrasulfonate. Role of the Alkylating Quinone 2,5-Dichloro-diaziridinyl-1,4-benzoquinone  

PubMed Central

Photoirradiation of nitrogen-saturated aqueous solutions containing aluminum phthalocyanine tetrasulfonate (AlPcS4) at 675 nm in the presence of 2,5-dichloro-diaziridinyl-1,4-benzoquinone (AZDClQ) and hypoxanthine (HX) produces the oxidized HX derivatives, xanthine (X) and uric acid (UA). Concentrations of the AZDClQ semiquinone, X and UA increase at the expense of HX with an increase in irradiation time. Almost negligible decomposition of HX, as well as very low amounts of X, are detected if photolysis occurs under identical conditions but in the absence of AZDClQ. Addition of calf-thymus DNA produces quinone-DNA covalent adducts after photolysis of anaerobic samples containing quinone, DNA and AlPcS4, in the presence or absence of HX and at pH 5.5. However, larger amounts of quinone-DNA adducts are detected if HX is present. The results presented here could have applications in the photodynamic treatment of hypoxic tissues such as solid tumors, under conditions of high HX concentration, where Type-I pathways could be more important than singlet oxygen generation. PMID:18627517

Alegria, Antonio E.; Inostroza, Yaritza; Kumar, Ajay

2009-01-01

126

Lesch-Nyhan variant syndrome: real-time rt-PCR for mRNA quantification in variable presentation in three affected family members.  

PubMed

Inherited mutations of hypoxanthine guanine phosphoribosyltransferase (HPRT) give rise to Lesch-Nyhan syndrome (LNS) or variants (LNV). We report molecular insights from real-time RT-PCR for HPRT mRNA quantification into the mechanism by which a single mutation located in exon 7 of the HPRT gene: c.500G>T, p.R167M, led to different clinical phenotypes from three male LNV-affected patients in the same family manifesting parallel differences in enzymatic activities. This approach can be applied for understanding genotype-phenotype correlations for other human genetic diseases. PMID:22908952

Nguyen, Khue Vu; Naviaux, Robert K; Paik, Kacie K; Nakayama, Tomohiro; Nyhan, William L

2012-01-01

127

Molecular cloning and nucleotide sequence for the complete coding region of human UMP synthase.  

PubMed Central

The last two steps in the de novo biosynthesis of UMP are catalyzed by orotate phosphoribosyltransferase (OPRT; orotidine-5'-phosphate:pyrophosphate phosphoribosyltransferase; EC 2.4.2.10) and orotidine-5'-monophosphate decarboxylase (orotidine-5'-phosphate carboxy-lyase; EC 4.1.1.23). In mammals these two activities are found in a single, bifunctional protein called UMP synthase. A human T-lymphoblastic cell cDNA library constructed in lambda gt10 was screened with a UMP synthase-specific rat cDNA probe. Human UMP synthase cDNAs were isolated and then used to select UMP synthase gene fragments. The complete coding sequence of the mRNA for UMP synthase was determined by analysis of overlapping cDNA and genomic fragments. One of the cDNAs appears to have been synthesized from an incompletely or alternatively processed form of the UMP synthase mRNA. This cDNA lacks a poly(A) tail and has an extended 3'-nontranslated region that hybridizes with larger forms of the UMP synthase mRNA. The UMP synthase protein is composed of 480 amino acids with a molecular weight of 52,199. The two activities of UMP synthase reside in distinct domains encoded by the 3' and 5' halves of the mRNA. The COOH-terminal 258 amino acids of the human UMP synthase protein contain the orotidine-5'-monophosphate decarboxylase catalytic domain. This region is highly homologous to the mouse orotidine-5'-monophosphate decarboxylase sequence. The NH2-terminal 214 amino acids contain the OPRT domain. There is amino acid homology between this protein domain and specific regions of the Escherichia coli OPRT. The human OPRT domain also contains the putative catalytic site common to other human phosphoribosyltransferases. PMID:3279416

Suttle, D P; Bugg, B Y; Winkler, J K; Kanalas, J J

1988-01-01

128

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

PubMed Central

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

Papakostas, Konstantinos; Botou, Maria; Frillingos, Stathis

2013-01-01

129

Surface Enhanced Raman Scattering of Whole Human Blood, Blood Plasma and Red Blood Cells: Cellular Processes and Bioanalytical Sensing  

PubMed Central

SERS spectra of whole human blood, blood plasma and red blood cells on Au nanoparticle SiO2 substrates excited at 785 nm have been observed. For the sample preparation procedure employed here, the SERS spectrum of whole blood arises from the blood plasma component only. This is in contrast to the normal Raman spectrum of whole blood excited at 785 nm and open to ambient air, which is exclusively due to the scattering of oxyhemoglobin. The SERS spectrum of whole blood shows a storage time dependence that is not evident in the non-SERS Raman spectrum of whole blood. Hypoxanthine, a product of purine degradation, dominates the SERS spectrum of blood after ~10 – 20 hours of storage at 8 °C. The corresponding SERS spectrum of plasma isolated from the stored blood shows the same temporal release of hypoxanthine. Thus, blood cellular components (red blood cells, white blood cells and/or platelets) are releasing hypoxanthine into the plasma over this time interval. The SERS spectrum of red blood cells (RBCs) excited at 785 nm is reported for the first time and exhibits well known heme group marker bands, as well as other bands that may be attributed to cell membrane components or protein denaturation contributions. SERS, as well as normal Raman spectra, of oxy- and met-RBCs are reported and compared. These SERS results can have significant impact in the area of clinical diagnostics, blood supply management and forensics. PMID:22780445

Premasiri, W. R.; Lee, J. C.; Ziegler, L. D.

2013-01-01

130

Analogues of 4-[(7-Bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methylprop-2-ynylamino]-N-(3-pyridylmethyl)benzamide (CB-30865) as potent inhibitors of nicotinamide phosphoribosyltransferase (Nampt).  

PubMed

We have shown previously that the target of the potent cytotoxic agent 4-[(7-bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methyl-prop-2-ynylamino]-N-(3-pyridylmethyl)benzamide (CB38065, 1) is nicotinamide phosphoribosyltransferase (Nampt). With its cellular target known we sought to optimize the biochemical and cellular Nampt activity of 1 as well as its cytotoxicity. It was found that a 3-pyridylmethylamide substituent in the A region was critical to cellular Nampt activity and cytotoxicity, although other aromatic substitution did yield compounds with submicromolar enzymatic inhibition. Small unsaturated groups worked best in the D-region of the molecule, with 3,3-dimethylallyl providing optimal potency. The E region required a quinazolin-4-one or 1,2,3-benzotriazin-4-one group for activity, and many substituents were tolerated at C² of the quinazolin-4-one. The best compounds showed subnanomolar inhibition of Nampt and low nanomolar cytotoxicity in cellular assays. PMID:21080724

Lockman, Jeffrey W; Murphy, Brett R; Zigar, Daniel F; Judd, Weston R; Slattum, Paul M; Gao, Zhong-Hua; Ostanin, Kirill; Green, Jeremy; McKinnon, Rena; Terry-Lorenzo, Ryan T; Fleischer, Tracey C; Boniface, J Jay; Shenderovich, Mark; Willardsen, J Adam

2010-12-23

131

Phenotypic changes and gene expression in human colon mucosal epithelial cells upon transfection of a SV40 DNA-gpt recombinant.  

PubMed

Phenotypic changes (increased longevity, decreased growth factor requirements, altered cell surface features, growth in semisolid agarose, and SV40 T antigen expression) suggesting in vitro transformation were displayed by human normal colon mucosal epithelial cells transfected with pSV3gpt, a pBR322 recombinant containing the SV40 "early" T antigen coding region and the dominant selectable marker bacterial gene, xanthine-guanine phosphoribosyltransferase. In contrast, control cultures which received neither DNA nor the recombinant pSV2gpt (which is identical to pSV3gpt but lacks the SV40 T antigen region) were not phenotypically altered. PMID:3029012

Moyer, M P; Aust, J B

1987-02-01

132

Mutagenicity of stereochemical configurations of 1,3-butadiene epoxy metabolites in human cells.  

PubMed

The mutagenic and carcinogenic effects of 1,3-butadiene (BD*) are related to its bioactivation to several DNA-reactive metabolites, including 1,2-epoxy-3-butene (BDO), 1,2,3,4-diepoxybutane (BDO2), and 1,2-dihydroxy-3,4-epoxybutane (BDO-diol). Accumulated evidence indicates that stereochemical configurations of BD metabolites may play a role in the mutagenic and carcinogenic action of BD. The objective of this study was to evaluate the cytotoxicity and mutagenicity of each stereoisomer of major BD metabolites in human cells. For this purpose, nine stereochemical forms of BDO, BDO2, and BDO-diol were synthesized. TK6 cells, a human lymphoblastoid cell line, were exposed to each stereoisomer. Cytotoxicity was measured by comparing cloning efficiencies (CEs) in chemical-exposed cells versus those in control cells. Based on the results of cytotoxicity tests, TK6 cells were exposed to 0; 2, 4, or 6 pM of each form of BDO2, or to 0, 200, 400, or 600 pMof each form of BDO for 24 hours to determine the mutagenic efficiencies. The exposure concentrations for BDO-diol ranged from 5 to 1000 pM. The mutagenicity was measured by determining, in a lymphocyte cloning assay, the mutant frequencies (Mfs) in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thymidine kinase (TK) genes. HPRT mutants collected from cells exposed to the three forms of BDO2 were analyzed by polymerase chain reaction (PCR) to characterize large genetic alterations. All three stereoisomers of BDO2 [(2R,3R)-BDO2, (2S,3S)-BDO2, and meso-BDO2] caused increased HPRT and TK Mfs compared with the concurrent control samples, with P values ranged from 0.05 to 0.001. There were no significant differences in cytotoxicity or mutagenicity among the three isomers of BDO2. Molecular analysis ofHPRTmutants revealed similar distributions of deletion mutations caused by the three isomers of BDO2. There were also no statistical differences in mutagenic efficiencies between the two isomers of BDO [(2R)-BDO and (2S)-BDO] in TK6 cells. These results were consistent with the in vivo finding that there was little difference in the mutagenic efficiencies of (+)-BDO2 versus meso-BDO2 in rodents. Thus, in terms of mutagenic potency, there was no evidence that stereochemical configurations of BDO and BDO2 play a significant role in the mutagenicity and carcinogenicity of BD. The most significant results of this study were the marked differences in cytotoxicity and mutagenicity among the four stereoisomers of BDO-diol [(2R,3R)-BDO-diol, (2R,3S)-BDO-diol, (2S,3R)-BDO-diol, and (2S,3S)-BDO-diol]. (2R,3S)-BDO-diol was at least 30-fold more cytotoxic and mutagenic than the other three forms of BDO-diol. This was consistent with the finding that 75% of the adduct N7-(2,3,4-trihydroxybutyl)guanine (THB-Gua) originated from (2R,3S)-BDO-diol in the lungs of mice exposed to BD. The mutagenic potency of (2R,3S)-BDO-diol was much closer to that of BDO2 than previously demonstrated in experiments in which stereochemistry was not considered. The current study demonstrated that the mutagenic potency of (2R,3S)-BDO-diol was only 5-to-l0-fold less than the average equimolar effect of BDO2 stereoisomers in the HPRT and TK genes, and was 10-to-20-fold greater than the average equimolar effect of BDO stereoisomers in the HPRT and TKgenes. Previous DNA and hemoglobin adduct data demonstrated that BDO-diol is the dominant BD metabolite available to react with macromolecules in vivo after BD exposure (Pérez et al. 1997; Swenberg et al. 2001). Thus, the differences in BD carcinogenesis among rodent species may be significantly accounted for by the stereochemistry-dependent distributions of BDO-diol metabolites and BDO-diol-DNA adducts, and by the mutagenic efficiencies of BDO-diol in mice and rats. PMID:20853577

Meng, Ryan Q; Hackfeld, Linda C; Hedge, Richard P; Wisse, Lynne A; Redetzke, Diana L; Walker, Vernon E

2010-06-01

133

Selective removal of ATP degradation products from food matrices II: Rapid screening of hypoxanthine and inosine by molecularly imprinted matrix solid-phase dispersion for evaluation of fish freshness.  

PubMed

A water compatible molecularly imprinted polymer (MIP), synthesized using theophylline (TPH) as dummy-template and acrylamide (AM) as functional monomer, has been employed as supporting material in matrix solid-phase dispersion combined with ultra performance liquid chromatography-photodiode array detection (MSPD-UPLC-PDA) for selective determination of adenosine triphosphate (ATP) derivatives in fish samples. ATP degradation products are used as freshness index for assessment of fish quality. The solid sample was directly blended with MIP in MSPD procedure resulting in sample disruption and subsequent adsorption of the compounds on the MIP. By using n-hexane and ammonium hydroxide aqueous solution at pH 9 as the washing and elution solvent, respectively, satisfactory recoveries and clean chromatograms have been obtained. Good linearity for hypoxanthine (HYP) and inosine (INO) has been observed with correlation coefficients (R(2)) of 0.9987 and 0.9986, respectively. The recoveries of the two ATP derivatives at three different spiked levels ranged from 106.5% to 113.4% for HYP and from 103.1% to 111.2% for INO, with average relative standard deviations lower than 4.2% in both cases. This new method, which is rapid, simple and sensitive, can be used as an alternative tool to conventional tedious methods. PMID:25640126

Cela-Pérez, M C; Barbosa-Pereira, L; Vecino, X; Pérez-Ameneiro, M; Latorre, Aurora Lasagabaster; López-Vilariño, J M; González Rodríguez, M V; Moldes, A B; Cruz, J M

2015-04-01

134

PRTFDC1 is a genetic modifier of HPRT-deficiency in the mouse.  

PubMed

Lesch-Nyhan disease (LND) is a severe X-linked neurological disorder caused by a deficiency of hypoxanthine phosphoribosyltransferase (HPRT). In contrast, HPRT-deficiency in the mouse does not result in the profound phenotypes such as self-injurious behavior observed in humans, and the genetic basis for this phenotypic disparity between HPRT-deficient humans and mice is unknown. To test the hypothesis that HPRT deficiency is modified by the presence/absence of phosphoribosyltransferase domain containing 1 (PRTFDC1), a paralog of HPRT that is a functional gene in humans but an inactivated pseudogene in mice, we created transgenic mice that express human PRTFDC1 in wild-type and HPRT-deficient backgrounds. Male mice expressing PRTFDC1 on either genetic background were viable and fertile. However, the presence of PRTFDC1 in the HPRT-deficient, but not wild-type mice, increased aggression as well as sensitivity to a specific amphetamine-induced stereotypy, both of which are reminiscent of the increased aggressive and self-injurious behavior exhibited by patients with LND. These results demonstrate that PRTFDC1 is a genetic modifier of HPRT-deficiency in the mouse and could therefore have important implications for unraveling the molecular etiology of LND. PMID:21818316

Keebaugh, Alaine C; Mitchell, Heather A; Gaval-Cruz, Meriem; Freeman, Kimberly G; Edwards, Gaylen L; Weinshenker, David; Thomas, James W

2011-01-01

135

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

SciTech Connect

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.

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

1995-12-01

136

COMPARISON OF MUTAGENICITY RESULTS FOR NINE COMPOUNDS EVALUATED AT THE HGPRT LOCUS IN THE STANDARD AND SUSPENSION CHO ASSAYS  

EPA Science Inventory

The Chinese hamster ovary (CHO) assay which measures newly induced mutations at the hypoxanthine-guanine phosphoribosyltransferase (hgprt) locus has been widely used for mutagenesis testing. he insensitivity of the standard assay to some genotoxic agents has been speculated to be...

137

Lesch–Nyhan disease and the basal ganglia  

Microsoft Academic Search

The purpose of this review is to summarize emerging evidence that the neurobehavioral features of Lesch–Nyhan disease (LND), a developmental disorder caused by congenital deficiency of the purine salvage enzyme hypoxanthine–guanine phosphoribosyltransferase (HPRT), may be attributable to dysfunction of the basal ganglia. Affected individuals have severe motor disability described by prominent extrapyramidal features that are characteristic of dysfunction of the

J. E Visser; P. R Bär; H. A Jinnah

2000-01-01

138

SOS-dependent A-->G transitions induced by hydroxyl radical generating system hypoxanthine/xanthine oxidase/Fe3+/EDTA are accompanied by the increase of Fapy-adenine content in M13 mp18 phage DNA.  

PubMed

Gas chromatography/isotope dilution-mass spectrometry with selected ion monitoring (GC/IDMS-SIM) was used to measure oxidised bases in hypoxanthine/xanthine oxidase/Fe3+/EDTA modified ss M13 mp18 phage DNA. A dose-dependent increase of oxidised bases content in DNA was observed with the biggest augmentation of FapyGua, thymine glycol and FapyAde. The amount of 8-OH-Gua was relatively high both in non-oxidised and oxidised DNA, and increased to the same extent as FapyAde and ThyGly. DNA oxidation caused a dramatic decrease in phage survival after transfection to E. coli. Survival was improved 2.8-fold after induction of the SOS system by UV irradiation of bacteria and mutation frequency of the lacZ gene in SOS conditions increased 7-fold over that in non-irradiated bacteria. Spectrum of mutations was different from those reported previously and mutations were distributed rather randomly within M13 lacZ sequence, which was in contrast to previous findings, where with non-chelated metal ions other types of mutations were found in several clusters. Thus, conditions of DNA oxidation and accessibility of metal ions for DNA bases might be important factors for generating different DNA damages and mutations. Major base substitutions found both in SOS-induced and non-induced E. coli but with higher mutation frequency in SOS-induced cells were C-->A (approximately 20-fold increase in SOS-conditions), G-->A (9-fold increase) and G-->C (4.5-fold increase). Very few G-->T transitions were found. A particularly large group of A-->G transitions appeared only in SOS-induced bacteria and was accompanied by augmentation of FapyAde content in the phage DNA with undetectable 2-OH-Ade. It is then possible that imidazole ring-opened adenine mimics guanine during DNA replication and pairs with cytosine yielding A-->G transitions in SOS-induced bacteria. PMID:10377947

Graziewicz, M A; Zastawny, T H; Oli?ski, R; Tudek, B

1999-05-14

139

Monochromosomal hybrids for the analysis of the human genome  

SciTech Connect

In this research project the authors proposed to develop rodent/human hybrid cell lines each containing a single different human chromosome. The human chromosomes will be marked with Ecogpt and stably maintained by selection in the hybrid cells. The experimental approach to produce the proposed cell lines involve the following: they will first transfer a cloned selectable marker, Ecogpt (an E. coli gene for xanthine-guanine phosphoribosyltransferase: XGPRT) to normal diploid human cells using a retroviral vector. The transferred gene will integrate at random into multiple sites in the recipient cell genome. Clonal cell lines from independent transgenotes will each carry the selectable marker integrated into a different site and perhaps a different chromosome. The chromosome carrying the selectable marker will then be transferred further to mouse cells by microcell fusion. In addition they also use directed integration of Ecogpt into the chromosome present in rodent cells, otherwise not marked with a selectable marker. This allows them to complete the bank of proposed cell line. The human chromosome, since it will be marked with a selectable marker, can be transferred to any other cell line of interest for complementation analysis. Clones of each cell line, containing varying size segments of the same chromosome produced by selection for the retention or loss of the selectable marker following x-irradiation or by metaphase chromosome transfer method will facilitate physical mapping and determination of gene order on a chromosome. 1 fig.

Athwal, R.S.

1990-01-01

140

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

SciTech Connect

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.

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

2006-01-01

141

Genotype-phenotype correlations in Lesch-Nyhan disease: moving beyond the gene.  

PubMed

Lesch-Nyhan disease and its attenuated variants are caused by mutations in the HPRT1 gene, which encodes the purine recycling enzyme hypoxanthine-guanine phosphoribosyltransferase. The mutations are heterogeneous, with more than 400 different mutations already documented. Prior efforts to correlate variations in the clinical phenotype with different mutations have suggested that milder phenotypes typically are associated with mutants that permit some residual enzyme function, whereas the most severe phenotype is associated with null mutants. However, multiple exceptions to this concept have been reported. In the current studies 44 HPRT1 mutations associated with a wide spectrum of clinical phenotypes were reconstructed by site-directed mutagenesis, the mutant enzymes were expressed in vitro and purified, and their kinetic properties were examined toward their substrates hypoxanthine, guanine, and phosphoribosylpyrophosphate. The results provide strong evidence for a correlation between disease severity and residual catalytic activity of the enzyme (k(cat)) toward each of its substrates as well as several mechanisms that result in exceptions to this correlation. There was no correlation between disease severity and the affinity of the enzyme for its substrates (K(m)). These studies provide a valuable model for understanding general principles of genotype-phenotype correlations in human disease, as the mechanisms involved are applicable to many other disorders. PMID:22157001

Fu, Rong; Jinnah, H A

2012-01-27

142

Molecular Structure of 6-Mercaptopurine  

NSDL National Science Digital Library

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.

2002-09-12

143

Identification of mutations leading to the Lesch-Nyhan syndrome by automated direct DNA sequencing of in vitro amplified cDNA  

Microsoft Academic Search

The Lesch-Nyhan (LN) syndrome is a severe X chromosome-linked disease that results from a deficiency of the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT). The mutations leading to the disease are heterogeneous and frequently arise as de novo events. The authors have identified nucleotide alterations in 15 independently arising HPRT-deficiency cases by direct DNA sequencing of in vitro amplified HPRT cDNA.

R. A. Gibbs; Phinga Nguyen; L. J. McBride; S. M. Koepf; C. T. Caskey

1989-01-01

144

Urine alkalinization may be enough for the treatment of bilateral renal pelvis stones associated with Lesch-Nyhan syndrome.  

PubMed

Lesch-Nyhan syndrome is a rare sex-linked disorder of purine metabolism that is caused by a mutation in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene which causes marked hyperuricemia and hyperuricosuria, with signs of gouty arthritis and uric acid stone disease in early childhood. We report a case of renal pelvis calculi which was dissolved within 10 days of urine alkalinization and hydration. PMID:21331772

Oh, Mi Mi; Ham, Byeong Kuk; Kang, Seok Ho; Bae, Jae Hyun; Kim, Je Jong; Yoo, Ki Hwan; Yoon, Duck Ki; Moon, Du Geon

2011-10-01

145

Carrier and prenatal diagnosis of Lesch-Nyhan disease due to a defect in HPRT gene expression regulation.  

PubMed

Lesch-Nyhan disease (LND) is caused by lack of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity. Mutations in HPRT1 gene show variability in type and location within the gene, and in certain patients the HPRT coding sequence is normal and the molecular defect cannot be found. These patients presented a decreased HPRT1 expression of unknown cause. This is the first report of a carrier and prenatal diagnosis of LND due to a defect in HPRT gene expression regulation. PMID:23046577

Torres, Rosa J; Garcia, Marta G; Puig, Juan G

2012-12-15

146

Molecular characterization of a deletion in the HPRT1 gene in a patient with Lesch-Nyhan syndrome.  

PubMed

Lesch-Nyhan syndrome is caused by a deficiency of hypoxanthine phosphoribosyltransferase (HPRT) encoded by HPRT1. About 20% of patients have a deletion of HPRT1 and large deletions of HPRT1 are not always fully characterized at the molecular level. Here, we report on a case of Lesch-Nyhan syndrome with a 33-kb deletion involving exon 1 of HPRT1. This novel mutation is caused by a nonhomologous recombination between different classes of interspersed repetitive DNA. PMID:22132985

Taniguchi, A; Yamada, Y; Hakoda, M; Sekita, C; Kawamoto, M; Kaneko, H; Yamanaka, H

2011-12-01

147

Delineation of the motor disorder of Lesch-Nyhan disease  

Microsoft Academic Search

Lesch-Nyhan disease (LND) is caused by deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Affected individuals exhibit over-production of uric acid, along with a characteristic neurobehavioural syndrome that includes mental retardation, recurrent self-injurious behaviour and motor disability. Prior studies involving relatively small numbers of patients have provided different conclusions on the nature of the motor disorder. The current study

H. A. Jinnah; Jasper E. Visser; James C. Harris; Alfonso Verdu; Laura Larovere; I. Ceballos-Picot; P. Gonzalez-Alegre; V. Neychev; R. J. Torres; O. Dulac; I. Desguerre; D. J. Schretlen; K. L. Robey; G. Barabas; B. R. Bloem; W. L. Nyhan; R. Kremer; G. E. Eddey; J. G. Puig; S. G. Reich

2006-01-01

148

Lesch Nyhan syndrome: a novel complex mutation in a Tunisian child.  

PubMed

Lesch Nyhan syndrome (LNS) is an X-linked recessive disorder due to complete deficiency of the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme. Defect of the enzymatic activity is related to mutations of the HPRT1 gene. The disorder severity is due to neurological features and renal complications. Up to now, more than 300 mutations have been reported. We report on a Tunisian child with a severe phenotype due to a novel identified complex mutation. PMID:24503445

Rebai, Ibtihel; Kraoua, Ichraf; Benrhouma, Hanene; Rouissi, Aida; Turki, Ilhem; Ceballos-Picot, Irène; Gouider-Khouja, Neziha

2014-11-01

149

Mutation analysis and prenatal diagnosis in a Lesch-Nyhan family showing non-random X-inactivation interfering with carrier detection tests  

Microsoft Academic Search

A nonsense mutation at the CpG-site in the codon for Arg(169) in the gene for hypoxanthine phosphoribosyltransferase (hprt) was identified by genomic polymerase chain reaction (PCR) and DNA sequencing in cultured fibroblasts from two brothers with Lesch Nyhan's syndrome. The recurrence of mutation at this CpG-site in several unrelated Lesch-Nyhan families suggests that deamination of 5-methylcytosine is a possible mechanism

Suzanne Marcus; Ann-Marie Steen; Björn Andersson; Bo Lambert; Ulf Kristoffersson; Uta Francke

1992-01-01

150

Lesch-Nyhan syndrome: mRNA expression of HPRT in patients with enzyme proven deficiency of HPRT and normal HPRT coding region of the DNA.  

PubMed

Inherited mutation of the purine salvage enzyme, hypoxanthine guanine phosphoribosyltransferase (HPRT) gives rise to Lesch-Nyhan syndrome (LNS) or Lesch-Nyhan variants (LNV). We report a case of two LNS affected members of a family with deficiency of activity of HPRT in intact cultured fibroblasts in whom mutation could not be found in the HPRT coding sequence but there was markedly decreased HPRT expression of mRNA. PMID:22766437

Nguyen, Khue Vu; Naviaux, Robert K; Paik, Kacie K; Nyhan, William L

2012-08-01

151

Transcriptomic approach to Lesch-Nyhan disease.  

PubMed

Lesch-Nyhan disease (LND) is an X-linked metabolic disease caused by various mutations in the gene HPRT1 encoding an enzyme of purine metabolism, hypoxanthine guanine phosphoribosyltransferase (HPRT). In its most severe form, LND patients suffer from overproduction of uric acid along with neurological or behavioural difficulties including self-injurious behaviours. To gain more insight into pathogenesis, we compared the transcriptome from human LND fibroblasts to normal human fibroblasts using a microarray with 60,000 probes corresponding to the entire human genome. Using stringent criteria, we identified 25 transcripts whose expression was significantly different between LND and control cells. These genes were confirmed by quantitative RT-PCR to be dysregulated in LND cells. Moreover, bioinformatic analysis of microarray data using gene ontology (GO) highlighted clusters of genes displaying biological processes most significantly affected in LND cells. These affected genes belonged to specific processes such as cell cycle and cell-division processes, metabolic and nucleic acid processes, demonstrating the specific nature of the changes and providing new insights into LND pathogenesis. PMID:24940671

Dauphinot, Luce; Mockel, Lionel; Cahu, Julie; Jinnah, H A; Ledroit, Morgan; Potier, Marie-Claude; Ceballos-Picot, Irène

2014-01-01

152

Transcriptomic Approach to Lesch-Nyhan Disease  

PubMed Central

Lesch-Nyhan disease (LND) is an X-linked metabolic disease caused by various mutations in the gene HPRT1 encoding an enzyme of purine metabolism, hypoxanthine guanine phosphoribosyltransferase (HPRT). In its most severe form, LND patients suffer from overproduction of uric acid along with neurological or behavioural difficulties including self-injurious behaviours. To gain more insight into pathogenesis, we compared the transcriptome from human LND fibroblasts to normal human fibroblasts using a microarray with 60,000 probes corresponding to the entire human genome. Using stringent criteria, we identified 25 transcripts whose expression was significantly different between LND and control cells. These genes were confirmed by quantitative RT-PCR to be dysregulated in LND cells. Moreover, bioinformatic analysis of microarray data using gene ontology (GO) highlighted clusters of genes displaying biological processes most significantly affected in LND cells. These affected genes belonged to specific processes such as cell cycle and cell-division processes, metabolic and nucleic acid processes, demonstrating the specific nature of the changes and providing new insights into LND pathogenesis. PMID:24940671

Dauphinot, Luce; Mockel, Lionel; Cahu, Julie; Jinnah, H. A.; Ledroit, Morgan; Potier, Marie-Claude; Ceballos-Picot, Irène

2014-01-01

153

Human HPRT mutant database: software for data entry and retrieval.  

PubMed

We have developed a computer database containing information on over 1,000 human hypoxanthine guanine phosphoribosyl transferase (HPRT) mutants. Both published and unpublished data are present. The database itself is maintained in a dBASE format (.DBF) and we provide a set of programs to examine and extract information from the database. A program to input information into the database is also supplied. The database and programs are available directly from us or via remote FTP (file transfer protocol) using BITNET/INTERNET. All programs require an IBM-compatible computer, the MS-DOS operating system (version 3.3 or greater), and a hard disk with about 5 megabytes of free disk space. The purpose of the database is 1) to allow investigators to contribute their HPRT mutants directly to the database in a standardized fashion, and 2) to allow access to the entire database with a set of programs that allows manipulation and extraction of data. For example, using our programs it is possible to i) order the database by base pair position, ii) examine only information regarding mutagenesis by a particular agent, iii) search for a particular author, iv) create a report which contains selected portions of the database, the report can be printed or saved as a file. The database will be updated every several months and distributed. PMID:1505531

Cariello, N F; Craft, T R; Vrieling, H; van Zeeland, A A; Adams, T; Skopek, T R

1992-01-01

154

40 CFR 158.2083 - Experimental use permit biochemical pesticides human health assessment data requirements table.  

Code of Federal Regulations, 2013 CFR

...lymphoma L5178Y cells, thymidine kinase (tk) gene locus, maximizing assay conditions for...hypoxanthine-guanine phosphoribosyl transferase (hgprt) gene locus, accompanied by an appropriate in...xanthine-guanine phosphoribosyl transferase (xprt) gene...

2013-07-01

155

40 CFR 158.2050 - Biochemical pesticides human health assessment data requirements table.  

Code of Federal Regulations, 2012 CFR

...lymphoma L5178Y cells, thymidine kinase (tk) gene locus, maximizing assay conditions for...hypoxanthine-guanine phosphoribosyl transferase (hgprt) gene locus, accompanied by an appropriate in...xanthine-guanine phosphoribosyl transferase (xprt) gene locus. 12. Required if there...

2012-07-01

156

40 CFR 158.2050 - Biochemical pesticides human health assessment data requirements table.  

...lymphoma L5178Y cells, thymidine kinase (tk) gene locus, maximizing assay conditions for...hypoxanthine-guanine phosphoribosyl transferase (hgprt) gene locus, accompanied by an appropriate in...xanthine-guanine phosphoribosyl transferase (xprt) gene locus. 12. Required if there...

2014-07-01

157

40 CFR 158.2083 - Experimental use permit biochemical pesticides human health assessment data requirements table.  

Code of Federal Regulations, 2012 CFR

...lymphoma L5178Y cells, thymidine kinase (tk) gene locus, maximizing assay conditions for...hypoxanthine-guanine phosphoribosyl transferase (hgprt) gene locus, accompanied by an appropriate in...xanthine-guanine phosphoribosyl transferase (xprt) gene...

2012-07-01

158

40 CFR 158.2083 - Experimental use permit biochemical pesticides human health assessment data requirements table.  

Code of Federal Regulations, 2010 CFR

...lymphoma L5178Y cells, thymidine kinase (tk) gene locus, maximizing assay conditions for...hypoxanthine-guanine phosphoribosyl transferase (hgprt) gene locus, accompanied by an appropriate in...xanthine-guanine phosphoribosyl transferase (xprt) gene...

2010-07-01

159

40 CFR 158.2050 - Biochemical pesticides human health assessment data requirements table.  

Code of Federal Regulations, 2010 CFR

...lymphoma L5178Y cells, thymidine kinase (tk) gene locus, maximizing assay conditions for...hypoxanthine-guanine phosphoribosyl transferase (hgprt) gene locus, accompanied by an appropriate in...xanthine-guanine phosphoribosyl transferase (xprt) gene locus. 12. Required if there...

2010-07-01

160

40 CFR 158.2083 - Experimental use permit biochemical pesticides human health assessment data requirements table.  

Code of Federal Regulations, 2011 CFR

...lymphoma L5178Y cells, thymidine kinase (tk) gene locus, maximizing assay conditions for...hypoxanthine-guanine phosphoribosyl transferase (hgprt) gene locus, accompanied by an appropriate in...xanthine-guanine phosphoribosyl transferase (xprt) gene...

2011-07-01

161

40 CFR 158.2050 - Biochemical pesticides human health assessment data requirements table.  

Code of Federal Regulations, 2013 CFR

...lymphoma L5178Y cells, thymidine kinase (tk) gene locus, maximizing assay conditions for...hypoxanthine-guanine phosphoribosyl transferase (hgprt) gene locus, accompanied by an appropriate in...xanthine-guanine phosphoribosyl transferase (xprt) gene locus. 12. Required if there...

2013-07-01

162

40 CFR 158.2083 - Experimental use permit biochemical pesticides human health assessment data requirements table.  

...lymphoma L5178Y cells, thymidine kinase (tk) gene locus, maximizing assay conditions for...hypoxanthine-guanine phosphoribosyl transferase (hgprt) gene locus, accompanied by an appropriate in...xanthine-guanine phosphoribosyl transferase (xprt) gene...

2014-07-01

163

40 CFR 158.2050 - Biochemical pesticides human health assessment data requirements table.  

Code of Federal Regulations, 2011 CFR

...lymphoma L5178Y cells, thymidine kinase (tk) gene locus, maximizing assay conditions for...hypoxanthine-guanine phosphoribosyl transferase (hgprt) gene locus, accompanied by an appropriate in...xanthine-guanine phosphoribosyl transferase (xprt) gene locus. 12. Required if there...

2011-07-01

164

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

PubMed Central

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

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

2013-01-01

165

Generation and Characterization of Mouse Hybridomas Secreting Monoclonal Antibodies Specific for Human IgG3  

PubMed Central

Mammalians express several subclasses of the IgG molecule. In human being there are four homologous IgG subclasses, each of which is structurally unique and has different functions. Quantification of IgG subclasses is fundamental to clinical assessment and diagnosis of many diseases as such assessments depends on the availability of subclassspecific antibodies (Abs), particularly monoclonal antibodies (MAbs). In the present study, we produced and characterized two murine MAbs specific for human IgG3 molecule. These MAbs were obtained by the fusion of myeloma cells with splenocytes from Balb/c mice immunized with heavy chain of a human IgG3 myeloma protein. Fused cells were selected in hypoxanthine, aminopterine and thymidine (HAT) medium and cloned by limiting dilution assay. Ab-secreting cells were screened by enzyme-linked immunosorbent assay (ELISA) and the specificity of secreted MAbs was further analyzed, using a panel of purified myeloma proteins by ELISA and immunoblotting. Two stable hybridomas designated 1F18G7 and 1F18A11 were obtained secreting MAbs specific for Fc fragment of human IgG3. None of these MAbs showed cross-reactivity with other immunoglobulin isotypes derived from human and nine other animals, except 1F18A11 which displayed a weak cross-reactivity with only dog serum. Immunoblotting results indicate that these MAbs react with linear epitope(s) located in the heavy chain of human IgG3 molecules. The affinity constant of 1F18G7 and 1F18A11 MAbs was found to be 0.81×109 Mol ?1 and 0.71×109 Mol ?1, respectively, as measured by ELISA. These two MAbs with relatively high affinity can be useful tools for quantification of IgG3 subclass levels in human serum. PMID:23407435

Hajighasemi, Fatemeh; Shokri, Fazel

2009-01-01

166

Expression and regulation of INTELECTIN1 in human granulosa-lutein cells: role in IGF-1-induced steroidogenesis through NAMPT.  

PubMed

INTELECTIN (ITLN) is an adipokine involved in the regulation of insulin sensitivity and inflammatory and immunity responses. Serum ITLN levels are lower in obese, diabetic, and polycystic ovary syndrome (PCOS) women than in control subjects. ITLN has never been studied in ovarian cells. Here, we identified ITLN1 in human ovarian follicles and investigated the molecular mechanisms involved in the regulation of its expression in response to the insulin sensitizers metformin and rosiglitazone, in human granulosa-lutein cells (hGLCs) and in a human ovarian granulosa-like tumor cell line (KGN). We also studied the effects of human recombinant ITLN1 (hRom1) on steroid production and on the activation of various signaling pathways. Using RT-PCR, immunoblotting, and immunohistochemistry, we found that INTL1 is present in human follicular cells. Using ELISA, we showed that INTL levels are similar in plasma and follicular fluid (FF) in control patients, whereas they are higher in FF than in plasma in PCOS patients. In KGN cells and hGLCs, insulin (10(-8) M), insulin-like growth factor-1 (IGF-1; 10(-8) M), and metformin (10(-2) M or 10(-3) M) increased INTL1 expression (mRNA and protein) after 12 and 24 h of stimulation. For metformin, this effect was mediated by adenosine monophosphate-activated kinase (PRKA). Furthermore, hRom1 increased nicotinamide phosphoribosyltransferase (NAMPT) expression in KGN and hGLCs. We also showed that hRom1 increased IGF-1-induced progesterone and estradiol secretion and this was associated with an increase in the STAR and CYP19A1 protein levels and an increase in IGF-1R signaling. Furthermore, all these data were abolished when NAMPT was knocked down in KGN cells, suggesting that INTL1 improves IGF-1-induced steroidogenesis through induction of NAMPT in hGLCs. PMID:24943040

Cloix, Lucie; Reverchon, Maxime; Cornuau, Marion; Froment, Pascal; Ramé, Christelle; Costa, Caroline; Froment, Gisèle; Lecomte, Pierre; Chen, Wenyong; Royère, Dominique; Guerif, Fabrice; Dupont, Joëlle

2014-08-01

167

Molecular structure and antioxidant specificity of purpurogallin in three types of human cardiovascular cells.  

PubMed

Purpurogallin (PPG) in an active cytoprotector found in certain oak barks. We have shown that PPG prolongs the survival of cultured cardiocytes from rats and rabbits against different oxidants better than do antioxidants such as Trolox (a hydrophilic analogue of vitamin E) in a morphometric assay system. First, we verified by X-ray crystallography that PPG is a bicyclic molecule comprising a phenolic ring fused with a seven-membered ring in a highly planar conformation. In analogues of PPG wherein the two double bonds in the seven membered ring of the parent molecule are saturated or where the four OH groups of the parent compound are substituted by four OCH3 groups, the derivatives are less planar and less protective of the human cells than native PPG. Second, PPG in a concentration-dependent manner protected myocytes and endothelial cells of humans against oxyradicals generated with any one of the following oxyradical generators: (a) xanthine oxidase plus hypoxanthine, (b) menadione, or (c) paraquat. In each case, PPG was more cytoprotective than comparative antioxidants. Also, PPG protected erythrocytes against peroxyl radicals better than the two PPG derivatives mentioned. Third, the cytoprotective action of PPG detected in vitro was accompanied by declines of malondialdehyde. Finally, we observed that PPG chelated ferrous ions and, therefore, can suppress the formation of radicals in the Fenton reaction. Thus, PPG with its molecular architecture and presumably its affinity for ferrous ions protects multiple types of cardiovascular cells against oxyradicals. PMID:8831727

Wu, T W; Zeng, L H; Wu, J; Fung, K P; Weisel, R D; Hempel, A; Camerman, N

1996-10-11

168

Mutations Associated with Functional Disorder of Xanthine Oxidoreductase and Hereditary Xanthinuria in Humans  

PubMed Central

Xanthine oxidoreductase (XOR) catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid with concomitant reduction of either NAD+ or O2. The enzyme is a target of drugs to treat hyperuricemia, gout and reactive oxygen-related diseases. Human diseases associated with genetically determined dysfunction of XOR are termed xanthinuria, because of the excretion of xanthine in urine. Xanthinuria is classified into two subtypes, type I and type II. Type I xanthinuria involves XOR deficiency due to genetic defect of XOR, whereas type II xanthinuria involves dual deficiency of XOR and aldehyde oxidase (AO, a molybdoflavo enzyme similar to XOR) due to genetic defect in the molybdenum cofactor sulfurase. Molybdenum cofactor deficiency is associated with triple deficiency of XOR, AO and sulfite oxidase, due to defective synthesis of molybdopterin, which is a precursor of molybdenum cofactor for all three enzymes. The present review focuses on mutation or chemical modification studies of mammalian XOR, as well as on XOR mutations identified in humans, aimed at understanding the reaction mechanism of XOR and the relevance of mutated XORs as models to estimate the possible side effects of clinical application of XOR inhibitors. PMID:23203137

Ichida, Kimiyoshi; Amaya, Yoshihiro; Okamoto, Ken; Nishino, Takeshi

2012-01-01

169

Influence of DNA Repair on Nonlinear Dose-Responses for Mutation  

PubMed Central

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

Johnson, George E.

2013-01-01

170

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

PubMed Central

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

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

1990-01-01

171

A comprehensive untargeted metabonomic analysis of human steatotic liver tissue by RP and HILIC chromatography coupled to mass spectrometry reveals important metabolic alterations.  

PubMed

Steatosis, or excessive accumulation of lipids in the liver, is a generally accepted previous step to the development of more severe conditions like nonalcoholic steatohepatitis, fibrosis, and cirrhosis. We aimed to characterize the metabolic profile that defines simple steatosis in human tissue and to identify potential disturbances in the hepatic metabolism that could favor the switch to progressive liver damage. A total of 46 samples, 23 from steatotic and 23 from nonsteatotic human livers, were analyzed following a holistic LC-MS-based metabonomic analysis that combines RP and HILIC chromatographic separations. Multivariate statistical data analysis satisfactorily classified samples and revealed steatosis-associated biomarkers. Increased levels of bile acids and phospholipid degradation products, and decreased levels of antioxidant species, were found in steatotic livers, indicating disturbances in lipid and bile acid homeostasis and mitochondrial dysfunction. Changes in hypoxanthine, creatinine, glutamate, glutamine, or ?-glutamyl-dipeptides concentrations, suggestive of alterations in energy metabolism and amino acid metabolism and transport, were also found. The results show that the proposed analytical strategy is suitable to achieve a comprehensive metabolic profile of steatotic human liver tissue and provide new insights into the metabolic alterations occurring in fatty liver that could contribute to its predisposition to damage evolution. PMID:21830829

García-Cañaveras, Juan C; Donato, M Teresa; Castell, José V; Lahoz, Agustín

2011-10-01

172

Molecular cloning of the human UMP synthase gene and characterization of point mutations in two hereditary orotic aciduria families.  

PubMed Central

Uridine monophosphate (UMP) synthase is a bifunctional enzyme catalyzing the last two steps of de novo pyrimidine biosynthesis, orotate phosphoribosyltransferase (OPRT) and orotidine-5'-monophosphate decarboxylase (ODC). Loss of either enzymatic activity results in hereditary orotic aciduria, a rare autosomal recessive disorder characterized by retarded growth, anemia, and excessive urinary excretion of orotic acid. We have isolated the UMP synthase chromosomal gene from a lambdaEMBL-3 human genomic library and report a single-copy gene spanning approximately 15 kb. The UMP synthase genomic structure encodes six exons ranging in size from 115 bp to 672 bp, and all splicing junctions adhere to the canonical GT/AG rule. Cognate promoter elements implicated in glucocorticoid- and cAMP-mediated regulation as well as in liver-, myeloid-, and lymphocyte-specific expression are located within the 5' flanking sequence. Molecular investigation of UMP synthase deficiency in a Japanese orotic aciduria patient revealed mutations R96G (A-to-G transition; nt 286) and G429R (G-to-C transversion; nt 1285) in one allele and V109G (T-to-G transversion; nt 326) in the other allele. Expression of human UMP synthase cDNAs containing these mutations in pyrimidine auxotrophic Escherichia coli and in recombinant baculovirus-infected Sf21 cells demonstrates impaired activity presumably associated with the urinary orotic acid substrate accumulations observed in vivo. We further establish the identity of two polymorphisms, G213A (v = .26) and 440Gpoly (v = .27) located in exons 3 and 6, respectively, which did not significantly compromise either OPRT or ODC function. Images Figure 1 Figure 4 Figure 5 PMID:9042911

Suchi, M; Mizuno, H; Kawai, Y; Tsuboi, T; Sumi, S; Okajima, K; Hodgson, M E; Ogawa, H; Wada, Y

1997-01-01

173

Simultaneous determination of purine and pyrimidine metabolites in HPRT-deficient cell lines.  

PubMed

Genetic mutations in the purine salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HPRT), are known to cause Lesch-Nyhan syndrome and Kelley-Seegmiller syndrome. In patients, purine metabolism is different from that of normal persons. We have previously developed a method for simultaneously determining the concentration of purine and pyrimidine nucleosides and nucleotides. This system was applied to determine the concentrations of nucleosides and nucleotides in HPRT-deficient cell lines. The amount of inosine 5'-monophosphate (IMP) was different in Lesch-Nyhan syndrome, Kelley-Seegmiller syndrome, and control cell lines. The difference in the amount of IMP confirmed the mutation of the enzyme. PMID:22132983

Yamaoka, N; Inazawa, K; Inagawa, S; Yasuda, M; Mawatari, K; Nakagomi, K; Fujimori, S; Yamada, Y; Kaneko, K

2011-12-01

174

Late diagnosis of Lesch-Nyhan disease variant.  

PubMed

A 30-year-old man was referred for investigation and management of hyperuricaemia. History included recurrent nephrolithiasis and chronic gout with poor response to medical management. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) enzyme activity was investigated and found to be deficient confirming the diagnosis of Lesch-Nyhan disease. Hyperuricaemia was treated with allopurinol. To prevent nephrolithiasis, the patient was instructed to avoid dehydration and aim for a minimum urine output of 2 L/day. Urinary alkalinisation with potassium citrate was started. The patient was referred for genetic counselling. This case discusses the genetics, pathophysiology, clinical manifestations, diagnosis and management of HGPRT deficiency. PMID:24326440

Doucet, Brian Percy; Jegatheesan, Dev; Burke, John

2013-01-01

175

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 ...

176

Human Ecology Human ecology Research  

E-print Network

Human Ecology Impact of Human ecology Research Bonus Issue FROM SCHOLARSHIP TO POLICY MAKING OF HUMAN ECOLOGY APRIL 2005/VOLUME 33, NUMBER 1 #12;Human Ecology Volume 33, Number 1 April 2005 The New York State College of Human Ecology at Cornell University Lisa Staiano-Coico, Ph.D. Rebecca Q

Wang, Z. Jane

177

Humanity and human DNA.  

PubMed

Genetics has marked the second half of the 20th century by addressing such formidable problems as the identification of our genes and their role, their interaction with the environment, and even their therapeutic uses. The identification of genes raises questions about differences between humans and non-humans, as well as about the evolution towards trans-humanism and post-humanism. In practise, however, the main question concerns the limits of prenatal genetic diagnosis, not only on account of the seriousness of the affections involved but also because of the choice to be made between following-up the medical indication and engaging in a systematic public health strategy aimed at eliminating children with certain handicaps. History reminds us that genetic science has already been misused by political forces influenced by the ideas of eugenics, particularly in the Nazi period. We may wonder whether it is reasonable to formulate a judgement on the life of a child yet to be born, merely on the basis of a DNA analysis. My experience as a practising geneticist and my involvement in French politics forces me to stress the dangers of a new eugenics hiding behind a medical mask. As demonstrated by epigenetics, human beings cannot be reduced to their DNA alone. In our society, one of the problems concerns individuals whose lives may be considered by some as simply not worth living. Another problem is the place and the social significance of the handicapped amongst us. Fortunately, recent progresses in gene therapy, biotherapy, and even pharmacology, appear to be opening up promising therapeutic perspectives. We should bear in mind that the chief vocation of medical genetics, which fully belongs to the art of medicine, is to heal and to cure. This is precisely where genetics should concentrate its efforts software. PMID:22705070

Mattei, Jean-François

2012-10-01

178

Ex vivo Expansion of Human Adult Pancreatic Cells with Properties of Distributed Stem Cells by Suppression of Asymmetric Cell Kinetics  

PubMed Central

Transplantation therapy for type I diabetes (T1D) might be improved if pancreatic stem cells were readily available for investigation. Unlike macroscopic islets, pancreatic tissue stem cells could more easily access the retroperitoneal pancreatic environment and thereby might achieve more effective pancreatic regeneration. Unfortunately, whether the adult pancreas actually contains renewing stem cells continues as a controversial issue in diabetes research. We evaluated a new method developed in our lab for expanding renewing distributed stem cells (DSCs) from adult tissues as a means to provide more evidence for adult pancreatic stem cells, and potentially advance their availability for future clinical investigation. The new method was designed to switch DSCs from asymmetric self-renewal to symmetric self-renewal, which promotes their exponential expansion in culture with reduced production of differentiated cells. Called suppression of asymmetric cell kinetics (SACK), the method uses natural purine metabolites to accomplish the self-renewal pattern shift. The SACK purine metabolites xanthine, xanthosine, and hypoxanthine were evaluated for promoting expansion of DSCs from the pancreas of adult human postmortem donors. Xanthine and xanthosine were effective for deriving both pooled and clonal populations of cells with properties indicative of human pancreatic DSCs. The expanded human cell strains had signature SACK agent-suppressible asymmetric cell kinetics, produced Ngn3+ bipotent precursors for ?-cells and ?-cells, and were non-tumorigenic in immunodeficient mice. Our findings support the existence of pancreatic DSCs in the adult human pancreas and indicate a potential path to increasing their availability for future clinical evaluation. PMID:25197614

Paré, JF; Sherley, JL

2013-01-01

179

Genotoxicity of 2,6- and 3,5-Dimethylaniline in Cultured Mammalian Cells: The Role of Reactive Oxygen Species  

PubMed Central

Several alkylanilines with structures more complex than toluidines have been associated epidemiologically with human cancer. Their mechanism of action remains largely undetermined, and there is no reported evidence that it replicates that of multicyclic aromatic amines even though the principal metabolic pathways of P450-mediated hydroxylation and phase II conjugation are very similar. As a means to elucidate their mechanisms of action, lethality and mutagenicity in the adenine phosphoribosyltransferase (aprt +/?) gene induced in several Chinese hamster ovary cell types by 2,6- and 3,5-dimethylaniline (2,6-DMA, 3,5-DMA) and their N- and ring-hydroxyl derivatives (N-OH-2,6-DMA, N-OH-3,5-DMA, 2,6-DMAP, 3,5-DMAP) were assessed. Dose-response relationships were determined in the parental AA8 cell line, its repair-deficient UV5 subclone and other repair-deficient 5P3NAT2 or -proficient 5P3NAT2R9 subclones engineered to express mouse cytochrome P4501A2 (CYP1A2) and human N-acetyltransferase (NAT2), and also in AS52 cells harboring the bacterial guanine-hypoxanthine phosphoribosyltransferase (gpt) gene. Mutations in the gpt gene of AS52 cells were characterized and found to be dominated by G:C to A:T and A:T to G:C transitions. Separately, treatment of AS52 cells with N-OH-2,6-DMA, N-OH-3,5-DMA, 2,6-DMAP, 3,5-DMAP, and 3,5-DMAP led to intracellular production of reactive oxygen species (ROS) for at least 24h after removal of the mutagens in every case. Using the comet assay, DNA strand breaks were observed in a dose-dependent manner in AS52 cells when treated with each of the four N-OH-2,6-DMA, N-OH-3,5-DMA, 2,6-DMAP, and 3,5-DMAP derivatives. Comparative evaluation of the results indicates that the principal mechanism of mutagenic action is likely to be through redox cycling of intracellularly bound aminophenol/quinone imine structures to generate ROS rather than through formation of covalent DNA adducts. PMID:22831970

Chao, Ming-Wei; Kim, Min Young; Wogan, Gerald N.

2012-01-01

180

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)

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.

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

2002-01-01

181

Substrate Binding Pocket Residues of Human Alkyladenine-DNA Glycosylase Critical for Methylating Agent Survival  

PubMed Central

Human alkyladenine-DNA glycosylase (AAG) initiates base excision repair (BER) of alkylated and deaminated bases in DNA. Here, we assessed the mutability of the AAG substrate binding pocket, and the essentiality of individual binding pocket amino acids for survival of methylation damage. We used oligonucleotide-directed mutagenesis to randomize 19 amino acids, 8 of which interact with substrate bases, and created more than 4.5 million variants. We expressed the mutant AAG's in repair-deficient E. coli and selected for protection against the cytotoxicity of either methylmethane sulfonate (MMS) or methyl-lexitropsin (Me-lex), an agent that produces 3-methyladenine as the predominant base lesion. Sequence analysis of 116 methylation-resistant mutants revealed no substitutions for highly conserved Tyr127and His136. In contrast, one mutation, L180F, was greatly enriched in both the MMS- and Me-lex-resistant libraries. Expression of the L180F single mutant conferred 4.4-fold enhanced survival at the high dose of MMS used for selection. The homogeneous L180F mutant enzyme exhibited 2.2-fold reduced excision of 3-methyladenine and 7.3-fold reduced excision of 7-methylguanine from methylated calf thymus DNA. Decreased excision of methylated bases by the mutant glycosylase could promote survival at high MMS concentrations, where the capacity of downstream enzymes to process toxic BER intermediates may be saturated. The mutant also displayed 6.6-, and 3.0-fold reduced excision of 1,N6-ethenoadenine and hypoxanthine from oligonucleotide substrates, respectively, and a 1.7-fold increase in binding to abasic site-containing DNA. Our work provides in vivo evidence for the substrate binding mechanism deduced from crystal structures, illuminates the function of Leu180 in wild-type human AAG, and is consistent with a role for balanced expression of BER enzymes in damage survival. PMID:18706524

Chen, Cheng-Yao; Guo, Haiwei H.; Shah, Dharini; Blank, A.; Samson, Leona D.; Loeb, Lawrence A.

2014-01-01

182

Adenosine transport in peripheral blood lymphocytes from Lesch-Nyhan patients.  

PubMed Central

We postulated that adenosine function could be related to some of the neurological features of Lesch-Nyhan syndrome and therefore characterized adenosine transport in PBLs (peripheral blood lymphocytes) obtained from Lesch-Nyhan patients (PBL(LN)) and from controls (PBL(C)). Adenosine transport was significantly lower in PBL(LN) when compared with that in PBL(C) and a significantly lower number of high affinity sites for [(3)H]nitrobenzylthioinosine binding were quantified per cell ( B (max)) in PBL(LN) when compared with that in PBL(C). After incubation with 25 microM hypoxanthine, adenosine transport was significantly decreased in PBL(LN) with respect to PBL(C). Hypoxanthine incubation lowers [(3)H]nitrobenzylthioinosine binding in PBL(C), with respect to basal conditions, but does not affect it in PBL(LN). This indicates that hypoxanthine affects adenosine transport in control and hypoxanthine-guanine phosphoribosyltransferase-deficient cells by different mechanisms. PMID:14572307

Torres, Rosa J; Deantonio, Isabel; Prior, Carmen; Puig, Juan G

2004-01-01

183

Clinical severity in Lesch-Nyhan disease: the role of residual enzyme and compensatory pathways.  

PubMed

Mutations in the HPRT1 gene, which encodes the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt), cause Lesch-Nyhan disease (LND) and more mildly affected Lesch-Nyhan variants. Prior studies have suggested a strong correlation between residual hypoxanthine recycling activity and disease severity. However, the relevance of guanine recycling and compensatory changes in the de novo synthesis of purines has received little attention. In the current studies, fibroblast cultures were established for 21 healthy controls and 36 patients with a broad spectrum of disease severity related to HGprt deficiency. We assessed hypoxanthine recycling, guanine recycling, steady-state purine pools, and de novo purine synthesis. There was a strong correlation between disease severity and either hypoxanthine or guanine recycling. Intracellular purines were normal in the HGprt-deficient fibroblasts, but purine wasting was evident as increased purine metabolites excreted from the cells. The normal intracellular purines in the HGprt-deficient fibroblasts were likely due in part to a compensatory increase in purine synthesis, as demonstrated by a significant increase in purinosomes. However, the increase in purine synthesis did not appear to correlate with disease severity. These results refine our understanding of the potential sources of phenotypic heterogeneity in LND and its variants. PMID:25481104

Fu, Rong; Sutcliffe, Diane; Zhao, Hong; Huang, Xinyi; Schretlen, David J; Benkovic, Steve; Jinnah, H A

2015-01-01

184

Fossil humans 1 Fossil humans  

E-print Network

Fossil humans 1 Fossil humans All prehistoric skeletal remains of humans which are archeologically or fossilization of bone, and regardless of whether the remains may be classed as Homo sapi- ens sapiens of the Neanderthal speci- men in 1856. Fossil human remains have come prin- cipally from Europe, Asia, China, Java

Delson, Eric

185

The Human Spark: Being Human  

NSDL National Science Digital Library

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.

2012-06-12

186

ALDH16A1 is a novel non-catalytic enzyme that may be involved in the etiology of gout via protein–protein interactions with HPRT1  

PubMed Central

Gout, a common form of inflammatory arthritis, is strongly associated with elevated uric acid concentrations in the blood (hyperuricemia). A recent study in Icelanders identified a rare missense single nucleotide polymorphism (SNP) in the ALDH16A1 gene, ALDH16A1*2, to be associated with gout and serum uric acid levels. ALDH16A1 is a novel and rather unique member of the ALDH superfamily in relation to its gene and protein structures. ALDH16 genes are present in fish, amphibians, protista, bacteria but absent from archaea, fungi and plants. In most mammalian species, two ALDH16A1 spliced variants (ALDH16A1, long form and ALDH16A1_v2, short form) have been identified and both are expressed in HepG-2, HK-2 and HK-293 human cell lines. The ALDH16 proteins contain two ALDH domains (as opposed to one in the other members of the superfamily), four transmembrane and one coiled-coil domains. The active site of ALDH16 proteins from bacterial, frog and lower animals contain the catalytically important cysteine residue (Cys-302); this residue is absent from the mammalian and fish orthologs. Molecular modeling predicts that both the short and long forms of human ALDH16A1 protein would lack catalytic activity but may interact with the hypoxanthine-guanine phosphoribosyltransferase (HPRT1) protein, a key enzyme involved in uric acid metabolism and gout. Interestingly, such protein-protein interactions with HPRT1 are predicted to be impaired for the long or short forms of ALDH16A1*2. These results lead to the intriguing possibility that association between ALDH16A1 and HPRT1 may be required for optimal HPRT activity with disruption of this interaction possibly contributing to the hyperuricemia seen in ALDH16A1*2 carriers. PMID:23348497

Vasiliou, Vasilis; Sandoval, Monica; Backos, Donald S.; Jackson, Brian C.; Chen, Ying; Reigan, Philip; Lanaspa, Miguel A.; Johnson, Richard J.; Koppaka, Vindhya; Thompson, David C.

2013-01-01

187

Deficiency of the purine metabolic gene HPRT dysregulates microRNA-17 family cluster and guanine-based cellular functions: a role for EPAC in Lesch-Nyhan syndrome.  

PubMed

Lesch-Nyhan syndrome (LNS) is a neurodevelopmental disorder caused by mutations in the gene encoding the purine metabolic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). A series of motor, cognitive and neurobehavioral anomalies characterize this disease phenotype, which is still poorly understood. The clinical manifestations of this syndrome are believed to be the consequences of deficiencies in neurodevelopmental pathways that lead to disordered brain function. We have used microRNA array and gene ontology analysis to evaluate the gene expression of differentiating HPRT-deficient human neuron-like cell lines. We set out to identify dysregulated genes implicated in purine-based cellular functions. Our approach was based on the premise that HPRT deficiency affects preeminently the expression and the function of purine-based molecular complexes, such as guanine nucleotide exchange factors (GEFs) and small GTPases. We found that several microRNAs from the miR-17 family cluster and genes encoding GEF are dysregulated in HPRT deficiency. Most notably, our data show that the expression of the exchange protein activated by cAMP (EPAC) is blunted in HPRT-deficient human neuron-like cell lines and fibroblast cells from LNS patients, and is altered in the cortex, striatum and midbrain of HPRT knockout mouse. We also show a marked impairment in the activation of small GTPase RAP1 in the HPRT-deficient cells, as well as differences in cytoskeleton dynamics that lead to increased motility for HPRT-deficient neuron-like cell lines relative to control. We propose that the alterations in EPAC/RAP1 signaling and cell migration in HPRT deficiency are crucial for neuro-developmental events that may contribute to the neurological dysfunctions in LNS. PMID:23804752

Guibinga, Ghiabe-Henri; Murray, Fiona; Barron, Nikki; Pandori, William; Hrustanovic, Gorjan

2013-11-15

188

Deficiency of the purine metabolic gene HPRT dysregulates microRNA-17 family cluster and guanine-based cellular functions: a role for EPAC in Lesch-Nyhan syndrome  

PubMed Central

Lesch-Nyhan syndrome (LNS) is a neurodevelopmental disorder caused by mutations in the gene encoding the purine metabolic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). A series of motor, cognitive and neurobehavioral anomalies characterize this disease phenotype, which is still poorly understood. The clinical manifestations of this syndrome are believed to be the consequences of deficiencies in neurodevelopmental pathways that lead to disordered brain function. We have used microRNA array and gene ontology analysis to evaluate the gene expression of differentiating HPRT-deficient human neuron-like cell lines. We set out to identify dysregulated genes implicated in purine-based cellular functions. Our approach was based on the premise that HPRT deficiency affects preeminently the expression and the function of purine-based molecular complexes, such as guanine nucleotide exchange factors (GEFs) and small GTPases. We found that several microRNAs from the miR-17 family cluster and genes encoding GEF are dysregulated in HPRT deficiency. Most notably, our data show that the expression of the exchange protein activated by cAMP (EPAC) is blunted in HPRT-deficient human neuron-like cell lines and fibroblast cells from LNS patients, and is altered in the cortex, striatum and midbrain of HPRT knockout mouse. We also show a marked impairment in the activation of small GTPase RAP1 in the HPRT-deficient cells, as well as differences in cytoskeleton dynamics that lead to increased motility for HPRT-deficient neuron-like cell lines relative to control. We propose that the alterations in EPAC/RAP1 signaling and cell migration in HPRT deficiency are crucial for neuro-developmental events that may contribute to the neurological dysfunctions in LNS. PMID:23804752

Guibinga, Ghiabe-Henri; Murray, Fiona; Barron, Nikki; Pandori, William; Hrustanovic, Gorjan

2013-01-01

189

Human Anatomy  

NSDL National Science Digital Library

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 ...

Schultz, Ms.

2007-11-09

190

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

NASA Technical Reports Server (NTRS)

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.

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

1994-01-01

191

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

NASA Astrophysics Data System (ADS)

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.

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

1994-10-01

192

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

NASA Technical Reports Server (NTRS)

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.

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

1994-01-01

193

Neuronal traits of clonal cell lines derived by fusion of dorsal root ganglia neurons with neuroblastoma cells.  

PubMed Central

In an attempt to immortalize the gene products of single neurons, somatic cell hybrids were produced by fusion of embryonic rat dorsal root ganglion (DRG) neurons with mouse neuroblastoma cells. Embryonic day 13 rat DRGs were fused with mouse neuroblastoma cells deficient in hypoxanthine phosphoribosyltransferase (HPRT; IMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.8). The hybrid cells were selected in medium with 100 microM hypoxanthine/1 microM aminopterin/12 microM thymidine to eliminate the neuroblastoma cells and with cis-hydroxyproline to retard fibroblast growth. Of the 17 lines derived, 4 manifested neuronal properties and were cloned. These lines retain both rat and mouse chromosomes and synthesize characteristic rat and mouse isoenzymes. Neuronal gangliosides, action potentials, and extensive neurite-like processes are exhibited by these hybrid cells, properties characteristic of DRG neurons but not of the neuroblastoma parent. Each line manifests a unique combination of action-potential properties and cell-surface markers, suggesting the selective expression of subsets of DRG neuronal genes. All of these neuronal properties are expressed constitutively, without the need for chemical induction or mitotic inhibition, and stably, without diminution after at least 5 months in culture. These lines may prove useful in the identification and isolation of gene products that characterize individual or small subsets of DRG neurons. Images PMID:3858835

Platika, D; Boulos, M H; Baizer, L; Fishman, M C

1985-01-01

194

Effect of TEI-6720, a xanthine oxidase inhibitor, on the nucleoside transport in the lung cancer cell line A549.  

PubMed

To examine the effect of 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid (TEI-6720), an inhibitor of xanthine oxidase, on purine metabolism in the lung cancer cell line A549, the activities of adenosine deaminase, purine nucleoside phosphorylase, adenine phosphoribosyltransferase, hypoxanthine guanine phosphoribosyltransferase, xanthine oxidase, and guanase together with pyrimidine nucleoside phosphorylase were measured with or without the addition of TEI-6720, and the extracellular concentrations of hypoxanthine, xanthine, inosine, uracil, and uridine were measured after the addition of inosine or uridine to the incubation medium with or without TEI-6720. Moreover, the Na-independent nucleoside transport was determined in A549 cells with or without TEI-6720. TEI-6720 inhibited the activity of xanthine oxidase in A549 cells, but did not affect other enzymes. During incubation, TEI-6720 not only prevented a decrease in the inosine concentration in inosine-containing medium, but also a decrease in the uridine concentration in uridine-containing medium. Furthermore, the Na-independent transport of uridine was inhibited by TEI-6720 with a K(i) value of 4.1 micromol/l. These results indicate that TEI-6720 is an inhibitor of the Na-independent nucleoside transport of uridine and inosine, as well as xanthine oxidase. PMID:10629441

Yamamoto, T; Moriwaki, Y; Fujimura, Y; Takahashi, S; Tsutsumi, Z; Tsutsui, T; Higashino, K; Hada, T

2000-01-01

195

Maternal low-protein diet alters the expression of real-time quantitative polymerase chain reaction reference genes in an age-, sex-, and organ-dependent manner in rat offspring.  

PubMed

Altered perinatal environment, often manifested as low birth weight, is thought to contribute to greater susceptibility for hypertension, hyperlipidemia, and diabetes as a result of epigenetic modifications and alteration of transcriptional activity for key genes. Real-time polymerase chain reaction is a useful technique for the quantitative determination of differences in transcriptional activity. Real-time quantitative polymerase chain reaction data analyses require normalization of transcriptional activity of target genes to an endogenous control, usually a reference gene. In response to reports of altered expression of reference genes in various experimental models, we hypothesized that adverse perinatal environment alters reference gene expression. We examined the expression of the following reference genes in the offspring of a rodent maternal low-protein diet model: ?-actin, hypoxanthine phosphoribosyltransferase 1, TATA-box-binding protein, glyceraldehyde-3-phosphate dehydrogenase, and glucuronidase-? in brain, heart, kidneys, and intestines. We found altered expression in brain, heart, and kidneys for each of the reference genes measured; these effects were age, organ, and sex dependent. Glyceraldehyde-3-phosphate dehydrogenase and glucuronidase-? were found to be the least affected by these variables, whereas hypoxanthine phosphoribosyltransferase 1 was the most inconsistent. Our findings underscore the importance of empirical determination of a reliable reference gene for real-time polymerase chain reaction studies in the low-protein diet model. PMID:23507230

DuBois, Barent; Pearson, Jacob; Hastings, Bonnie; Mahmood, Tahir; Chan, Tammy; Alnakhli, Ali; Cherala, Ganesh

2013-03-01

196

Normal uricemia in lesch-nyhan syndrome and the association with pulmonary embolism in a young child-a case report and literature review.  

PubMed

Deficiency of hypoxanthine phosphoribosyltransferase activity is a rare inborn error of purine metabolism with subsequent uric acid overproduction and neurologic presentations. The diagnosis of Lesch-Nyhan syndrome (LNS) is frequently delayed until self-mutilation becomes evident. We report the case of a boy aged 1 year and 10 months who was diagnosed with profound global developmental delay, persistent chorea, and compulsive self-mutilation since the age of 1 year. Serial serum uric acid levels showed normal uric acid level, and the spot urine uric acid/creatinine ratio was >2. The hypoxanthine phosphoribosyltransferase cDNA showed the deletion of exon 6, and the boy was subsequently diagnosed to have LNS. He also had respiratory distress due to pulmonary embolism documented by chest computed tomography scan. This report highlights the need to determine the uric acid/creatinine ratio caused by increased renal clearance in LNS in young children. The presence of pulmonary embolism is unusual and may be the consequence of prolonged immobilization. PMID:23597535

Tsai, Jeng-Dau; Chen, Shan-Ming; Lin, Chien-Heng; Ku, Min-Sho; Tsao, Teng-Fu; Sheu, Ji-Nan

2014-08-01

197

Manipulation of Cell Physiology Enables Gene Silencing in Well-differentiated Airway Epithelia.  

PubMed

The application of RNA interference-based gene silencing to the airway surface epithelium holds great promise to manipulate host and pathogen gene expression for therapeutic purposes. However, well-differentiated airway epithelia display significant barriers to double-stranded small-interfering RNA (siRNA) delivery despite testing varied classes of nonviral reagents. In well-differentiated primary pig airway epithelia (PAE) or human airway epithelia (HAE) grown at the air-liquid interface (ALI), the delivery of a Dicer-substrate small-interfering RNA (DsiRNA) duplex against hypoxanthine-guanine phosphoribosyltransferase (HPRT) with several nonviral reagents showed minimal uptake and no knockdown of the target. In contrast, poorly differentiated cells (2-5-day post-seeding) exhibited significant oligonucleotide internalization and target knockdown. This finding suggested that during differentiation, the barrier properties of the epithelium are modified to an extent that impedes oligonucleotide uptake. We used two methods to overcome this inefficiency. First, we tested the impact of epidermal growth factor (EGF), a known enhancer of macropinocytosis. Treatment of the cells with EGF improved oligonucleotide uptake resulting in significant but modest levels of target knockdown. Secondly, we used the connectivity map (Cmap) database to correlate gene expression changes during small molecule treatments on various cells types with genes that change upon mucociliary differentiation. Several different drug classes were identified from this correlative assessment. Well-differentiated epithelia treated with DsiRNAs and LY294002, a PI3K inhibitor, significantly improved gene silencing and concomitantly reduced target protein levels. These novel findings reveal that well-differentiated airway epithelia, normally resistant to siRNA delivery, can be pretreated with small molecules to improve uptake of synthetic oligonucleotide and RNA interference (RNAi) responses.Molecular Therapy - Nucleic Acids (2012) 1, e41; doi:10.1038/mtna.2012.36; published online 28 August 2012. PMID:23344182

Krishnamurthy, Sateesh; Behlke, Mark A; Ramachandran, Shyam; Salem, Aliasger K; McCray, Paul B; Davidson, Beverly L

2012-01-01

198

Manipulation of Cell Physiology Enables Gene Silencing in Well-differentiated Airway Epithelia  

PubMed Central

The application of RNA interference-based gene silencing to the airway surface epithelium holds great promise to manipulate host and pathogen gene expression for therapeutic purposes. However, well-differentiated airway epithelia display significant barriers to double-stranded small-interfering RNA (siRNA) delivery despite testing varied classes of nonviral reagents. In well-differentiated primary pig airway epithelia (PAE) or human airway epithelia (HAE) grown at the air–liquid interface (ALI), the delivery of a Dicer-substrate small-interfering RNA (DsiRNA) duplex against hypoxanthine–guanine phosphoribosyltransferase (HPRT) with several nonviral reagents showed minimal uptake and no knockdown of the target. In contrast, poorly differentiated cells (2–5-day post-seeding) exhibited significant oligonucleotide internalization and target knockdown. This finding suggested that during differentiation, the barrier properties of the epithelium are modified to an extent that impedes oligonucleotide uptake. We used two methods to overcome this inefficiency. First, we tested the impact of epidermal growth factor (EGF), a known enhancer of macropinocytosis. Treatment of the cells with EGF improved oligonucleotide uptake resulting in significant but modest levels of target knockdown. Secondly, we used the connectivity map (Cmap) database to correlate gene expression changes during small molecule treatments on various cells types with genes that change upon mucociliary differentiation. Several different drug classes were identified from this correlative assessment. Well-differentiated epithelia treated with DsiRNAs and LY294002, a PI3K inhibitor, significantly improved gene silencing and concomitantly reduced target protein levels. These novel findings reveal that well-differentiated airway epithelia, normally resistant to siRNA delivery, can be pretreated with small molecules to improve uptake of synthetic oligonucleotide and RNA interference (RNAi) responses. PMID:23344182

Krishnamurthy, Sateesh; Behlke, Mark A; Ramachandran, Shyam; Salem, Aliasger K; McCray Jr, Paul B; Davidson, Beverly L

2012-01-01

199

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

SciTech Connect

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.

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

1995-06-01

200

Alkyltransferase-mediated toxicity of bis-electrophiles in mammalian cells  

PubMed Central

The primary function of O6-alkylguanine-DNA alkyltransferase (AGT) is to maintain genomic integrity in the face of damage by both endogenous and exogenous alkylating agents. However, paradoxically, bacterial and mammalian AGTs have been shown to increase cytotoxicity and mutagenicity of dihaloalkanes and other bis-electrophiles when expressed in bacterial cells. We have extended these studies to mammalian cells using CHO cells that lack AGT expression and CHO cells stably transfected with a plasmid that expresses human AGT. The cytotoxicity of 1,2-dibromoethane, dibromomethane and epibromohydrin was significantly increased by the presence of AGT but cytotoxicity of butadiene diepoxide was not affected. Mutations caused by these agents were assessed using hypoxanthine-guanine phosphoribosyltransferase (HPRT) as a reporter gene. There was a small (c. 2–3-fold) but statistically significant AGT-mediated increase in mutations caused by 1,2-dibromoethane, dibromomethane and epibromohydrin. Analysis of the mutation spectrum induced by 1,2-dibromoethane showed that the presence of AGT also altered the types of mutations with an increase in total base substitution mutants due to a rise in transversions at both G:C and A:T sites. AGT expression also led to mutations arising from the transcribed strand, which were not seen in cells lacking AGT. Although the frequency of deletion mutations was decreased by AGT expression, the formation of large deletions (?3 exons) was increased. This work demonstrates that interaction of AGT with some bis-electrophiles can cause mutagenicity and diminished cell survival in mammalian cells. It is consistent with the hypothesis that DNA-AGT cross-links, which have been characterized in experiments with purified AGT protein and such bis-electrophiles, can be formed in mammalian cells. PMID:19941875

Kalapila, Aley G.; Pegg, Anthony E.

2009-01-01

201

Interstellar humanity  

Microsoft Academic Search

Fifty years after Olaf Stapledon's landmark essay “Interplanetary man?”, we propose the coming era of “interstellar humanity”. Over the next 1000 years the domain of humanity will increasingly spread to the stars, a process that will alter our future in profound ways. At least three factors will drive this expansion: (1) increased understanding of cosmic evolution, changing our perception of

Steven J Dick

2000-01-01

202

Inhibition of De Novo Purine Biosynthesis and Interconversion by 6-Methylpurine in Escherichia coli  

PubMed Central

The inhibition of Escherichia coli strain B and strain W-11 by 6-methylpurine depended on the formation of 6-methylpurine ribonucleotide by the action of adenine phosphoribosyltransferase (AMP: pyrophosphate phosphoribosyltransferase, EC 2.4.2.7). 6-Methylpurine ribonucleotide inhibited the de novo synthesis of purines, presumably via pseudofeedback inhibition of phosphoribosylpyrophosphate amidotransferase (EC 2.4.2.14). The same mechanism accounted for its inhibition of adenylosuccinate synthetase [IMP: l-aspartate ligase (GDP), EC 6.3.4.4]. Adenine and 6-methylaminopurine prevented inhibition by competing for the action of adenine phosphoribosyltransferase. In addition, adenine reversed this inhibition by replenishing the AMP to bypass both sites of inhibition. Nonproliferating suspensions of strain B-94, which lacked adenylosuccinate lyase (EC 4.3.2.2), converted exogenous hypoxanthine and aspartate to succinoadenine derivatives which accumulated in the medium. Compounds which inhibited adenylosuccinate synthetase inhibited accumulation of the succinoadenine derivatives. A method was described for the isolation of mutants which potentially possessed an altered adenylosuccinate synthetase. PMID:4908785

Benson, Charles E.; Love, Samuel H.; Remy, Charles N.

1970-01-01

203

Water: Human Health  

MedlinePLUS

... Quality Standards Water Quality Criteria Human Health Criteria Human Health Criteria Human health ambient water quality criteria ... Updated National Recommended Water Quality Criteria - Human Health Human Health Research Program Human Health Research provides the ...

204

Human Papillomavirus and Human Disease  

Microsoft Academic Search

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

1997-01-01

205

Human Evolution  

NSDL National Science Digital Library

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.

Lee, Amy.

2002-01-01

206

Human rhinoviruses.  

PubMed

Human rhinoviruses are the most important causative agents of upper respiratory infections and are also implicated in more severe clinical entities. Although often present, very little is known about human rhinoviruses. Molecular methods have been used in the classification of this large group of viruses into two separate clades. In addition, one known serotype was found to be a member of enterovirus group D. Laboratory diagnosis of human rhinovirus infection is based on reverse transcription polymerase chain reaction methods or the more tedious virus culture but a rapid "bedside" method is unavailable. Anti-rhinoviral therapy has been under extensive study over the past few decades but symptomatic treatment of the common cold is still the only useful approach in clinical use. More data on circulating human rhinovirus strains would facilitate both detection and treatment of these common pathogens. PMID:12758045

Savolainen, Carita; Blomqvist, Soile; Hovi, Tapani

2003-06-01

207

Human monkeypox.  

PubMed

Human monkeypox is a zoonotic Orthopoxvirus with a presentation similar to smallpox. Clinical differentiation of the disease from smallpox and varicella is difficult. Laboratory diagnostics are principal components to identification and surveillance of disease, and new tests are needed for a more precise and rapid diagnosis. The majority of human infections occur in Central Africa, where surveillance in rural areas with poor infrastructure is difficult but can be accomplished with evidence-guided tools and educational materials to inform public health workers of important principles. Contemporary epidemiological studies are needed now that populations do not receive routine smallpox vaccination. New therapeutics and vaccines offer hope for the treatment and prevention of monkeypox; however, more research must be done before they are ready to be deployed in an endemic setting. There is a need for more research in the epidemiology, ecology, and biology of the virus in endemic areas to better understand and prevent human infections. PMID:24158414

McCollum, Andrea M; Damon, Inger K

2014-01-01

208

Human Anatomy  

NSDL National Science Digital Library

The EMuseum at the University of Minnesota-Mankato provides this educational site on human anatomy. Although some parts of the site are still under construction, the Introduction to the Skeletal System section offers a straightforward introduction to the topic, complete with black-and-white skeletal photographs. Topics in this section include skeletal functions, axial and appendicular divisions, types of bone, bone composition, and a brief list of anatomical terms. For educators of introductory human anatomy, this site should provide interesting supplemental information.

209

Behavior, human.  

PubMed

Human behavior is the collection of actions or reactions exhibited by human beings in relation to the environment, and it can be categorized as either innate or learned. In psychology, behavior became an important construct with the advent of behaviorism, a theoretical framework that required the study of only observable facts or events which can be seen or manipulated, in response to external or internal stimuli. More recently, the Relational Frame Theory (RFT) suggests that also some psychological events such as thoughts and emotions can be explained as learned responses. In TACT project, behavior is the voluntary movement of reaching and grasping in a fixed condition. PMID:20393688

Molteni, M

2010-01-01

210

Classical Humanities  

ERIC Educational Resources Information Center

This article reports on a pilot course in humanities team-taught by three teachers, two from a senior high-school and one from a junior high-school, in Brookfield, Wisconsin. The specific subject matter is Greek and Roman culture. The curriculum is outlined and the basic reading list is included. (CLK)

Goodwin, Donn; And Others

1975-01-01

211

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.

212

Nothing Human  

ERIC Educational Resources Information Center

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…

Wharram, C. C.

2014-01-01

213

Human Effect  

NSDL National Science Digital Library

In this lesson, students will investigate changes in air quality due to human interaction particularly burning of fossil fuels, and crop burning which increase levels of carbon monoxide. Students will evaluate changes in air quality over a 6 month time frame using Air Quality-Carbon Monoxide Data and draw conclusions based on observing color plot comparison graphs.

214

Human Trafficking  

ERIC Educational Resources Information Center

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

Wilson, David McKay

2011-01-01

215

Human Ectoparasites  

NSDL National Science Digital Library

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).

Sohmer, Rachel.

216

Introduction Human Development/Human Devel-  

E-print Network

20 Introduction Guide Entrance Life Career Inquiries Human Development/Human Devel- opment a sustainable society that allows us to maintain our humanity. Japan faces pressing issues such as rapid issues, the GraduateSchoolofHumanDevelopmentandEnvironment and the Faculty of Human Development

Banbara, Mutsunori

217

Human Capital, (Human) Capabilities and Higher Education  

ERIC Educational Resources Information Center

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

Le Grange, L.

2011-01-01

218

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.

219

Human Traits  

NSDL National Science Digital Library

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.

Irene Salter

2012-06-26

220

Human genetics  

SciTech Connect

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.

Carlson, E.A.

1984-01-01

221

Human mastication  

Microsoft Academic Search

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

G. Slavicek

2010-01-01

222

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 ...

223

Modeled microgravity affects cell survival and HPRT mutant frequency, but not the expression of DNA repair genes in human lymphocytes irradiated with ionising radiation  

Microsoft Academic Search

We analysed the possibility that a reduced gravitational force impairs the efficiency of DNA repair, increasing the risk of the exposure to conditions occurring during spaceflight: i.e., ionising radiation and microgravity. To obtain information on the effects of the reduced gravity in repairing DNA damage induced by radiation, we compared cell survival and mutant frequency at the hypoxanthine-guanine phosphoribosyl transferase

Maddalena Mognato; Lucia Celotti

2005-01-01

224

Human Propulsion  

NSDL National Science Digital Library

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.

Pratte, John

225

Teaching Human Rights: Evaluating Human Rights Education  

Microsoft Academic Search

Human rights education (HRE) is currently discussed as one of the key means to establish sustainable and long-term stable societies. HRE contributes to the dissemination of the Universal Declaration of Human Rights (UDHR) from 1948 and to help creating a culture of Human Rights. There are dozens of international legal human rights frameworks such as conventions and treaties of the

Anja Mihr

226

Human Subjects Section 6. Protection of Human  

E-print Network

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

Heller, Barbara

227

The Digital Humanities as a Humanities Project  

ERIC Educational Resources Information Center

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

Svensson, Patrik

2012-01-01

228

Validation of Endogenous Control Genes for Gene Expression Studies on Human Ocular Surface Epithelium  

PubMed Central

Purpose To evaluate a panel of ten known endogenous control genes (ECG) with quantitative reverse transcription PCR (qPCR), for identification of stably expressed endogenous control genes in the ocular surface (OS) epithelial regions including cornea, limbus, limbal epithelial crypt and conjunctiva to normalise the quantitative reverse transcription PCR data of genes of interest expressed in above-mentioned regions. Method The lasermicrodissected (LMD) OS epithelial regions of cryosectioned corneoscleral buttons from the cadaver eyes were processed for RNA extraction and cDNA synthesis to detect genes of interest with qPCR. Gene expression of 10 known ECG—glyceraldehyde-3-phosphate dehydrogenase (GAPDH), beta actin (ACTB), peptidylprolyl isomerase (PPIA), TATA-box binding protein (TBP1), hypoxanthine guanine phosphoribosyl transferase (HPRT1), beta glucuronidase (GUSB), Eucaryotic 18S ribosomal RNA (18S), phosphoglycerate kinase (PGK1), beta-2-microglobulin (B2M), ribosomal protein, large, P0 (RPLP0)—was measured in the OS epithelial regions by qPCR method and the data collected was further analysed using geNorm software. Results The expression stability of ECGs in the OS epithelial regions in increasing order as determined with geNorm software is as follows: ACTB<18Shuman OS epithelium and provide evidence for the use of PPIA-RPLP0 ECGs pair in quantitative reverse transcription PCR across the OS epithelium. PMID:21857920

Kulkarni, Bina; Mohammed, Imran; Hopkinson, Andrew; Dua, Harminder Singh

2011-01-01

229

Novel assay for simultaneous measurement of pyridine mononucleotides synthesizing activities allows dissection of the NAD(+) biosynthetic machinery in mammalian cells.  

PubMed

The redox coenzyme NAD(+) is also a rate-limiting co-substrate for several enzymes that consume the molecule, thus rendering its continuous re-synthesis indispensable. NAD(+) biosynthesis has emerged as a therapeutic target due to the relevance of NAD(+) -consuming reactions in complex intracellular signaling networks whose alteration leads to many neurologic and metabolic disorders. Distinct metabolic routes, starting from various precursors, are known to support NAD(+) biosynthesis with tissue/cell-specific efficiencies, probably reflecting differential expression of the corresponding rate-limiting enzymes, i.e. nicotinamide phosphoribosyltransferase, quinolinate phosphoribosyltransferase, nicotinate phosphoribosyltransferase and nicotinamide riboside kinase. Understanding the contribution of these enzymes to NAD(+) levels depending on the tissue/cell type and metabolic status is necessary for the rational design of therapeutic strategies aimed at modulating NAD(+) availability. Here we report a simple, fast and sensitive coupled fluorometric assay that enables simultaneous determination of the four activities in whole-cell extracts and biological fluids. Its application to extracts from various mouse tissues, human cell lines and plasma yielded for the first time an overall picture of the tissue/cell-specific distribution of the activities of the various enzymes. The screening enabled us to gather novel findings, including (a) the presence of quinolinate phosphoribosyltransferase and nicotinamide riboside kinase in all examined tissues/cell lines, indicating that quinolinate and nicotinamide riboside are relevant NAD(+) precursors, and (b) the unexpected occurrence of nicotinate phosphoribosyltransferase in human plasma. PMID:25223558

Zamporlini, Federica; Ruggieri, Silverio; Mazzola, Francesca; Amici, Adolfo; Orsomando, Giuseppe; Raffaelli, Nadia

2014-11-01

230

Human Factors in Human-Systems Integration  

NASA Technical Reports Server (NTRS)

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.

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

2008-01-01

231

Humane Education: An Overview.  

ERIC Educational Resources Information Center

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

Whitlock, Eileen S.; Westerlund, Stuart R.

232

Human Rhinoviruses  

PubMed Central

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

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

2013-01-01

233

Human Genetics: Careers in Human Genetics  

MedlinePLUS

Careers in Human Genetics What is genetics? Genetics is the study of genes, their functions, and their effects. Why become a ... demand for geneticists? As the details of the human genome unfold, the variety of opportunities for people ...

234

Human herpesvirus 8 – A novel human pathogen  

PubMed Central

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

Edelman, Daniel C

2005-01-01

235

HUMAN RESOURCES DISTRIBUTION RESTRICTION  

E-print Network

FM 1-0 HUMAN RESOURCES SUPPORT APRIL 2014 DISTRIBUTION RESTRICTION: Approved for public release...................................................................................................vi Chapter 1 HUMAN RESOURCES (HR) SUPPORT ........................................................... 1-1 Army Human Resources Command (HRC) ....................................................... 2-1 Army

US Army Corps of Engineers

236

Human Resource Management Concentration  

E-print Network

Human Resource Management Concentration While many rules and specific regulations apply to taking-requisite(s)...........................................................Semester(s) Offered Required Courses: MGT310............Human Resource Management........................................................................................fall MGT474............Human Resource Planning and Development .......MGT310

Barnes, Elizabeth A.

237

Human Papillomavirus (HPV)  

MedlinePLUS

... Preventable Diseases > Human Papillomavirus (HPV) Health Issues Listen Human Papillomavirus (HPV) Article Body According to the Centers ... Control and Prevention, there is an epidemic of human papillomavirus (HPV) in the United States. HPV is ...

238

Human-machine interactions  

DOEpatents

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.

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

239

Human Research Protection Program Plan  

E-print Network

Human Research Protection Program Plan Revised February 27, 2014 #12;Human Research Protection............................................................................................................... 4 Engaged in Human Research...................................................................................... 4 Human Research

Weber, David J.

240

Localisation of a new gene for non-specific mental retardation to Xq22-q26 (MRX35).  

PubMed Central

Non-specific mental retardation (MR) is a condition in which MR appears to be the only consistent manifestation. The X linked form (MRX) is genetically heterogeneous. We report clinical, cytogenetic, and linkage data on a family with X linked non-specific MR. Two point and multi-point linkage analysis with 18 polymorphic markers, covering the entire chromosome, showed close linkage to DXS1001 and DXS425 with a maximal lod score of 2.41 at 0% recombination. DXS178 and the gene for hypoxanthine phosphoribosyl-transferase (HPRT), located in Xq22 and Xq26 respectively, flank the mutation. All other chromosomal regions could be excluded with odds of at least 100:1. To our knowledge there is currently no other non-specific MR gene mapped to this region. Therefore, the gene causing MR in this family can be considered to be a new, independent MRX locus (MRX35). PMID:8825049

Gu, X X; Decorte, R; Marynen, P; Fryns, J P; Cassiman, J J; Raeymaekers, P

1996-01-01

241

Lateralized effect of pallidal stimulation on self-mutilation in Lesch-Nyhan disease.  

PubMed

Lesch-Nyhan disease (LND) is an X-linked hereditary disorder caused by a deficiency of hypoxanthine-guanine phosphoribosyltransferase. This syndrome is characterized by hyperuricemia, self-mutilation, cognitive impairment, and movement disorders such as spasticity and dystonia. The authors describe the case of a 15-year-old boy who underwent bilateral placement of globus pallidus internus (GPi) deep brain stimulation (DBS) electrodes for the treatment of generalized dystonia. His self-mutilating behavior gradually disappeared several weeks after the start of GPi stimulation. The dystonia and self-mutilating behavior returned on the left side only after a right lead fracture. This case is the first reported instance of LND treated with DBS in which the stimulation was interrupted and the self-mutilation returned in a lateralized fashion. The findings indicate that the neurobehavioral aspect of LND is lateralized and that contralateral GPi stimulation is responsible for lateralized improvement in self-injurious behavior. PMID:25303157

Abel, Taylor J; Dalm, Brian D; Grossbach, Andrew J; Jackson, Adam W; Thomsen, Teri; Greenlee, Jeremy D W

2014-12-01

242

Disorders of purines and pyrimidines.  

PubMed

Disorders of purine and pyrimidine metabolism can result in an array of clinical manifestations including neurologic manifestations. The most commonly cited disorder, in the neurologic realm, is Lesch-Nyhan syndrome which presumably reflects its distinctive feature of self-mutilation. Expansion of our knowledge with molecular genetic methodology has helped to better identify and characterize mutations such as those which occur with the enzyme hypoxanthine guanine phosphoribosyltransferase (HPRT), and this has enhanced our understanding of phenotypical expression of Lesch-Nyhan syndrome and Lesch-Nyhan variants. It is hoped that further elucidation of DNA coding regions and messenger RNA expression will lead to the potential for gene therapy to correct these inborn errors of purine and pyrimidine metabolism. PMID:24365355

Kelley, Roger E; Andersson, Hans C

2014-01-01

243

HPRT deficiency in Spain: what have we learned in the past 30 years (1984-2013)?  

PubMed

Since 1984, we have diagnosed at the La Paz University Hospital, Madrid, Spain, 41 patients with hypoxanthine phosphoribosyltransferase (HPRT) activity deficiency. These patients belonged to 34 families. We have also performed molecular and enzymatic diagnosis in three patients from India, one from Belgium, and three from Colombia. About 1/3 of these patients were followed up at La Paz University Hospital at least every year. This fact has allowed us to examine the complete spectrum of HPRT deficiency as well as to perform a more accurate diagnosis and treatment. In the present review, we also summarized our studies on the basis of physiopathology of the neurological manifestation of Lesch Nyhan disease (LND). PMID:24940673

Torres, R J; Prior, C; Garcia, M G; Beltran, L M; Puig, J G

2014-01-01

244

From genotype to phenotype; clinical variability in Lesch-Nyhan disease. The role of epigenetics.  

PubMed

Lesch-Nyhan disease is a rare genetic disease characterized by a deficiency in the function of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT). Patients affected by this disease experience hyperuricemia, motor disorders, mental retardation and, in the most severe cases, self-mutilation. Its clinical manifestations depend on the enzymatic activity of HGPRT, which is classically linked to the type of alteration in the HGPRT gene. More than 400 mutations of this gene have been found. At present, one of the controversial aspects of the disease is the relationship between the genotype and phenotype; cases have been described lacking a mutation, such as the patient presented in this article, as well as families who despite sharing the same genetic defect show disorders with differing severity. Epigenetic processes, which modify the genetic expression without changing the sequence of the deoxyribonucleic acid (DNA), could explain the clinical variability observed in this disease. PMID:24863549

Trigueros Genao, M; Torres, R J

2014-11-01

245

Identification of mutations leading to the Lesch-Nyhan syndrome by automated direct DNA sequencing of in vitro amplified cDNA  

SciTech Connect

The Lesch-Nyhan (LN) syndrome is a severe X chromosome-linked disease that results from a deficiency of the purine salvage enzyme hypoxanthine phosphoribosyltransferase (HPRT). The mutations leading to the disease are heterogeneous and frequently arise as de novo events. The authors have identified nucleotide alterations in 15 independently arising HPRT-deficiency cases by direct DNA sequencing of in vitro amplified HPRT cDNA. They also demonstrate that the direct DNA sequence analysis can be automated, further simplifying the detection of new mutations at this locus. The mutations include DNA base substitutions, small DNA deletions, a single DNA base insertion, and errors in RNA splicing. The application of these procedures allows DNA diagnosis and carrier identification by the direct detection of the mutant alleles within individual families affected by LN.

Gibbs, R.A. (Baylor College of Medicine, Houston, TX (USA)); Nguyen, Phinga (Howard Hughes Medical Institute, Houston, TX (USA)); McBride, L.J.; Koepf, S.M. (Applied Biosystems, Foster City, CA (USA)); Caskey, C.T. (Baylor College of Medicine, Houston, TX (USA) Howard Hughes Medical Institute, Houston, TX (USA))

1989-03-01

246

Update on the phenotypic spectrum of Lesch-Nyhan disease and its attenuated variants.  

PubMed

Congenital deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) results in a spectrum of clinical phenotypes. All of these phenotypes are associated with marked overproduction of uric acid and related problems such as hyperuricemia, urate nephrolithiasis, tophi, and gout. The mildest phenotypes include only problems related to overproduction of uric acid. The most severe phenotype is known as Lesch-Nyhan disease, in which the phenotype also includes severe motor handicap, intellectual disability, and self-injurious behavior. In between these two extremes is a continuous spectrum of phenotypes with varying degrees of motor and cognitive handicap but no self-injurious behavior. The pathogenesis of overproduction of uric acid in HPRT deficiency is well-understood, and treatments are available to control it. The pathogenesis of the neurobehavioral problems is less well-understood, and effective treatments for them are lacking. PMID:22198833

Torres, Rosa J; Puig, Juan G; Jinnah, H A

2012-04-01

247

HPV (Human Papillomavirus)  

MedlinePLUS

... papillomavirus test for primary cervical cancer screening HPV (human papillomavirus) Print and Share (PDF 1105 KB ) En Español HPV (human papillomavirus) is a sexually transmitted virus. It is ...

248

Pesticides and Human Health  

MedlinePLUS

... Ingredients Regulations State Federal International Environment Air Water Soil Wildlife Plants Emergency Human Poisonings Pet Poisoning Spills and Contamination Wildlife Poisoning / Environmental Incident Pesticide Incidents Human Exposure ...

249

MicroRNA-mediated dysregulation of neural developmental genes in HPRT deficiency: clues for Lesch-Nyhan disease?  

PubMed

Mutations in the gene encoding the purine biosynthetic enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) cause the intractable neurodevelopmental Lesch-Nyhan disease (LND) associated with aberrant development of brain dopamine pathways. In the current study, we have identified an increased expression of the microRNA miR181a in HPRT-deficient human dopaminergic SH-SY5Y neuroblastoma cells. Among the genes potentially regulated by miR181a are several known to be required for neural development, including Engrailed1 (En1), Engrailed2 (En2), Lmx1a and Brn2. We demonstrate that these genes are down-regulated in HPRT-deficient SH-SY5Y cells and that over-expression of miR181a significantly reduces endogenous expression of these genes and inhibits translation of luciferase plasmids bearing the En1/2 or Lmx1a 3'UTR miRNA-binding elements. Conversely, inhibition of miR181a increases the expression of these genes and enhances translation of luciferase constructs bearing the En1/2 and Lmx1a 3'UTR miRNA-binding sequences. We also demonstrate that key neurodevelopmental genes (e.g. Nurr1, Pitx3, Wnt1 and Mash1) known to be functional partners of Lmx1a and Brn2 are also markedly down-regulated in SH-SY5Y cells over-expressing miR181a and in HPRT-deficient cells. Our findings in SH-SY5Y cells demonstrate that HPRT deficiency is accompanied by dysregulation of some of the important pathways that regulate the development of dopaminergic neurons and dopamine pathways and that this defect is associated with and possibly due at least partly to aberrant expression of miR181a. Because aberrant expression of miR181a is not as apparent in HPRT-deficient LND fibroblasts, the relevance of the SH-SY5Y neuroblastoma cells to human disease remains to be proven. Nevertheless, we propose that these pleiotropic neurodevelopment effects of miR181a may play a role in the pathogenesis of LND. PMID:22042773

Guibinga, Ghiabe-Henri; Hrustanovic, Gorjan; Bouic, Kathryn; Jinnah, Hyder A; Friedmann, Theodore

2012-02-01

250

Human Computer Intelligent Interaction  

E-print Network

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

Chen, Sheng-Wei

251

Human Research Program Opportunities  

NASA Technical Reports Server (NTRS)

The goal of HRP is to provide human health and performance countermeasures, knowledge, technologies, and tools to enable safe, reliable, and productive human space exploration. The Human Research Program was designed to meet the needs of human space exploration, and understand and reduce the risk to crew health and performance in exploration missions.

Kundrot, Craig E.

2014-01-01

252

Humanism: A Christian Perspective.  

ERIC Educational Resources Information Center

As part of a four-college project to integrate the religious tradition with humanities teaching, humanism is discussed from a Christian perspective. Definitions of the terms humanism, religion, Christianity, and Christian humanism are provided. The latter is viewed as the issues surrounding the Christian approach to the dichotomy of good and evil…

Kaasa, Harris; And Others

253

Visualizing Humans by Computer.  

ERIC Educational Resources Information Center

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…

Magnenat-Thalmann, Nadia

1992-01-01

254

Human Reliability Engineering  

Microsoft Academic Search

Human reliability engineering (HRE) is the description, analysis, and improvement of situations in which human errors have been made or could be made. The probability of human error is distinguished from the probability of incident. HRE can be carried out at different levels: A. Prevention with regard to a future human error; B. Prevention of a future incident and correction

H. Kragt

1978-01-01

255

The Humanities: Interconnections.  

ERIC Educational Resources Information Center

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…

Salomone, Ronald E., Ed.

1985-01-01

256

Boundaries of Humanities: Writing Medical Humanities  

ERIC Educational Resources Information Center

Literature and medicine is a discipline within medical humanities, which challenges medicine to reconfigure its scientific model to become interdisciplinary, and be disciplined by arts and humanities as well as science. The psychological, emotional, spiritual and physical are inextricably linked in people, inevitably entailing provisionality,…

Bolton, Gillie

2008-01-01

257

Telling the Human Story.  

ERIC Educational Resources Information Center

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)

Richardson, Miles

1987-01-01

258

Climate and Human Evolution  

NSDL National Science Digital Library

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.

Foundation, Wgbh E.

2010-11-30

259

Patenting Human Evolution  

E-print Network

to thorough analysis and debate prior to the imminent arrival of human genetic enhancement technologies. Otherwise, patent law may drive human evolution in directions either unplanned - or worse - undesired....

Torrance, Andrew W.

2008-06-01

260

Biomedical Ethics & Medical Humanities  

E-print Network

BEMH Biomedical Ethics & Medical Humanities Scholarly Concentration Stanford University School? The Biomedical Ethics and Medical Humanities Scholarly Concentration is part of the new initiative at Stanford interactions, neonatology, issues of limited resources, ethics of medical advances, informed consent issues

Ford, James

261

Human Papillomavirus (HPV) Screening  

MedlinePLUS

... Search The CDC Cancel Submit Search The CDC Human Papillomavirus (HPV) Note: Javascript is disabled or is ... Associated Cancers Gynecologic Cancers HPV Screening Share Compartir Human papillomavirus (HPV) causes genital warts and cancers, such ...

262

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.

263

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.

264

Human Balance System  

MedlinePLUS

... support. 1 A properly functioning balance system allows humans to see clearly while moving, identify orientation with ... Dr. Daniel Merfeld, Massachusettes Eye & Ear Infirmary The human balance system involves a complex set of sensorimotor- ...

265

Human Parainfluenza Viruses  

MedlinePLUS

... Search The CDC Cancel Submit Search The CDC Human Parainfluenza Viruses (HPIVs) Note: Javascript is disabled or ... visit this page: About CDC.gov . Share Compartir Human parainfluenza viruses (HPIVs) commonly cause respiratory illnesses in ...

266

Pathfinder: Humans in space  

NASA Technical Reports Server (NTRS)

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

Anderson, John L.

1988-01-01

267

Electrophilic Aromatic Selenylation: New OPRT Inhibitors  

PubMed Central

2-Ethoxyethaneseleninic acid reacts with electron rich aromatic substrates to deliver, by way of the selenoxides, the (2-ethoxyethyl) seleno ethers, which can in turn be transformed into a diverse set of aryl selenylated products. Among these, a family of 5-uridinyl derivatives shows sub-micromolar inhibition of human and malarial orotate phosphoribosyltransferase. PMID:20521773

Abdo, Mohannad; Zhang, Yong; Schramm, Vern L.; Knapp, Spencer

2010-01-01

268

The Human Body  

NSDL National Science Digital Library

We will be learning about The Human Body! Think about these questions as you go through: How does the muscular system work? Why is the skeletal system important? Hello 4A! Our next unit is learning about The Human Body! I want you to explore and come up with a burning question you have about The Human Body! Here is a fun fact about The Human Body: A baby has 300 bones at birth. An adult has ...

Bratkiewicz, Miss

2011-12-10

269

To Err is Human  

Microsoft Academic Search

We argue for the importance of human error as a signif- icant and oft-overlooked factor in system dependability, and contend that human behavior must be considered in both dependability benchmarks and high-dependability system designs. We support our claims with data illus- trating that human-induced failures consistently account for half of all outages, and show that human error accompanies even the

Aaron B. Brown; David A. Patterson

2001-01-01

270

Human productivity program definition  

NASA Technical Reports Server (NTRS)

The optimization of human productivity on the space station within the existing resources and operational constraints is the aim of the Human Productivity Program. The conceptual objectives of the program are as follows: (1) to identify long lead technology; (2) to identify responsibility for work elements; (3) to coordinate the development of crew facilities and activities; and (4) to lay the foundation for a cost effective approach to improving human productivity. Human productivity work elements are also described and examples are presented.

Cramer, D. B.

1985-01-01

271

dGTP Starvation in Escherichia coli Provides New Insights into the Thymineless-Death Phenomenon  

PubMed Central

Starvation of cells for the DNA building block dTTP is strikingly lethal (thymineless death, TLD), and this effect is observed in all organisms. The phenomenon, discovered some 60 years ago, is widely used to kill cells in anticancer therapies, but many questions regarding the precise underlying mechanisms have remained. Here, we show for the first time that starvation for the DNA precursor dGTP can kill E. coli cells in a manner sharing many features with TLD. dGTP starvation is accomplished by combining up-regulation of a cellular dGTPase with a deficiency of the guanine salvage enzyme guanine-(hypoxanthine)-phosphoribosyltransferase. These cells, when grown in medium without an exogenous purine source like hypoxanthine or adenine, display a specific collapse of the dGTP pool, slow-down of chromosomal replication, the generation of multi-branched nucleoids, induction of the SOS system, and cell death. We conclude that starvation for a single DNA building block is sufficient to bring about cell death. PMID:24810600

Itsko, Mark; Schaaper, Roel M.

2014-01-01

272

Portraits of Human Greatness.  

ERIC Educational Resources Information Center

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…

Saint Anselm's Coll., Manchester, NH.

273

Faculty Affairs, Human Resources  

E-print Network

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

Finley Jr., Russell L.

274

Boston University Human Resources  

E-print Network

Boston University Human Resources 910 Commonwealth Avenue 3 rd Floor Boston, Massachusetts 02215 Memorandum To: Boston University Faculty and Staff From: Diane Tucker, Chief Human Resources Officer Date: August 5, 2013 Subject: Human Resources - On the Move In order to continue on improving our service model

Goldberg, Bennett

275

DEPARTMENT OF HUMAN RESOURCES  

E-print Network

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

Brownstone, Rob

276

Humanities 1 Professor Edwards  

E-print Network

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

Blanco, Philip R.

277

Humanities 4 Professor Watkins  

E-print Network

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

Blanco, Philip R.

278

Humanities 1 Department of  

E-print Network

.imperial.ac.uk/humanities/evening. Languages Arabic, French, German, Italian, Japanese, Mandarin, Russian and Spanish. Humanities Music and ethical dilemmas in science and technology Philosophy Creative writing Politics European history 1870­1989 Philosophies of science: theory, society and communication History of medicine Humanities essay Global history

279

Human Genetics Portfolio Review  

E-print Network

Human Genetics 1990­2009 June 2010 Portfolio Review #12;The Wellcome Trust is a charity registered in providing the assessments of the Wellcome Trust's role in supporting human genetics and have informed `our input to the development of the timelines. #12;Contents Portfolio Review: Human Genetics | 3

Rambaut, Andrew

280

Human Rights Educational Resources.  

ERIC Educational Resources Information Center

Gives a variety of educational resources on human rights that include videos, resource notebooks, books, publications, and websites along with short descriptions of the materials. Provides the contact information for a list of human-rights organizations, such as the Center for Human Rights Education and the Franklin and Eleanor Roosevelt…

Flowers, Nancy

1998-01-01

281

Dogs catch human yawns  

Microsoft Academic Search

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

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

2008-01-01

282

Demystifying the Humanities.  

ERIC Educational Resources Information Center

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…

Bonham, George

1980-01-01

283

Has Human Evolution Stopped?  

PubMed Central

It has been argued that human evolution has stopped because humans now adapt to their environment via cultural evolution and not biological evolution. However, all organisms adapt to their environment, and humans are no exception. Culture defines much of the human environment, so cultural evolution has actually led to adaptive evolution in humans. Examples are given to illustrate the rapid pace of adaptive evolution in response to cultural innovations. These adaptive responses have important implications for infectious diseases, Mendelian genetic diseases, and systemic diseases in current human populations. Moreover, evolution proceeds by mechanisms other than natural selection. The recent growth in human population size has greatly increased the reservoir of mutational variants in the human gene pool, thereby enhancing the potential for human evolution. The increase in human population size coupled with our increased capacity to move across the globe has induced a rapid and ongoing evolutionary shift in how genetic variation is distributed within and among local human populations. In particular, genetic differences between human populations are rapidly diminishing and individual heterozygosity is increasing, with beneficial health effects. Finally, even when cultural evolution eliminates selection on a trait, the trait can still evolve due to natural selection on other traits. Our traits are not isolated, independent units, but rather are integrated into a functional whole, so selection on one trait can cause evolution to occur on another trait, sometimes with mildly maladaptive consequences. PMID:23908778

Templeton, Alan R.

2010-01-01

284

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...

285

Intervention and Human Rights.  

ERIC Educational Resources Information Center

Defends the right of nations to criticize human rights violations within other nations. Pointing out that the human rights protections cannot be left to domestic jurisdiction, Goldberg cites numerous treaties and declarations which make human rights protection a matter of international law. (GEA)

Goldberg, Arthur J.

1988-01-01

286

Human Services Practicum Program.  

ERIC Educational Resources Information Center

This paper presents a university practicum program in human services and outlines the human services field instruction policies for course instructors. An orientation to the Human Services Practicum is followed by a discussion of the student field placement process. A set of educational objectives is listed to provide the practicum student with…

Alexander, Robert C.; Sabol, Edward J.

287

Production Of Human Antibodies  

NASA Technical Reports Server (NTRS)

Process for making human monoclonal antibodies based on combination of techniques. Antibodies made active against specific antigen. Process involves in vivo immunization of human B lymphocyte cells in mice. B cells of interest enriched in vitro before fusion. Method potentially applicable to any antigen. Does not rely on use of Epstein-Barr virus at any step. Human lymphocytes taken from any source.

Sammons, David W.; Neil, Garry A.

1993-01-01

288

HUMAN USE INDEX  

EPA Science Inventory

Human land uses may have major impacts on ecosystems, affecting biodiversity, habitat, air and water quality. The human use index (also known as U-index) is the percentage of human land use in an area, including agriculture, urban and suburban development, and mining. Low values ...

289

HUMAN USE INDEX (FUTURE)  

EPA Science Inventory

Human land uses may have major impacts on ecosystems, affecting biodiversity, habitat, air and water quality. The human use index (also known as U-index) is the percentage of human land use in an area, including agriculture, urban and suburban development, and mining. Low values ...

290

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 ...

291

Human Research ProgramHuman Research Program Human System Risk in Exploration and  

E-print Network

Human Research ProgramHuman Research Program Human System Risk in Exploration and the Human Research Program 21SEP10 1HRP Risk Process ­ D Grounds #12;Human Research ProgramHuman Research Program Human System Risks in Exploration Missions 21SEP10 2HRP Risk Process ­ D.Grounds Presentation contents

Waliser, Duane E.

292

Human Development The Division of Human Development provides  

E-print Network

358 Human Development The Division of Human Development provides multidisciplinary undergraduate and graduate programs that examine individual, social and structural aspects of human development. The programs is to foster students' understanding of complex human conditions. The division values diversity

Suzuki, Masatsugu

293

Human Performance in Space  

NASA Technical Reports Server (NTRS)

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.

Jones, Patricia M.; Fiedler, Edna

2010-01-01

294

Humans Are Like Robots  

NSDL National Science Digital Library

Four lessons related to robots and people present students with life sciences concepts related to the human body (including brain, nervous systems and muscles), introduced through engineering devices and subjects (including computers, actuators, electricity and sensors), via hands-on LEGO® robot activities. Students learn what a robot is and how it works, and then the similarities and differences between humans and robots. For instance, in lesson 3 and its activity, the human parts involved in moving and walking are compared with the corresponding robot components so students see various engineering concepts at work in the functioning of the human body. This helps them to see the human body as a system, that is, from the perspective of an engineer. Students learn how movement results from 1) decision making, such as deciding to walk and move, and 2) implementation by conveying decisions to muscles (human) or motors (robot).

2014-09-18

295

Human reliability analysis  

SciTech Connect

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.

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

1988-01-01

296

Annotated Webliography Of Humanism  

NSDL National Science Digital Library

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.

Derkx, Peter.

1998-01-01

297

Climate and Human Migrations  

NSDL National Science Digital Library

Access to the article is free, however registration and sign-in are required. About 14,600 years ago, humans first appeared in south central Chile. But the arid regions of the Atacama desert in northern Chile were not populated for another 2000 years, and human occupation of this region subsequently remained intermittent. In his Perspective, Dillehay highlights the report of Núñez et al., whose integrative archaeological and paleoecological study shows that climate was the key factor in these human migrations. The study illustrates the power of an integrative approach to understanding the relation between human societies and climate change.

Tom D. Dillehay (University of Kentucky; Department of Anthropology)

2002-10-25

298

Robotics for Human Exploration  

NASA Technical Reports Server (NTRS)

Robots can do a variety of work to increase the productivity of human explorers. Robots can perform tasks that are tedious, highly repetitive or long-duration. Robots can perform precursor tasks, such as reconnaissance, which help prepare for future human activity. Robots can work in support of astronauts, assisting or performing tasks in parallel. Robots can also perform "follow-up" work, completing tasks designated or started by humans. In this paper, we summarize the development and testing of robots designed to improve future human exploration of space.

Fong, Terrence; Deans, Mathew; Bualat, Maria

2013-01-01

299

Reflecting on Human Reflexes  

NSDL National Science Digital Library

Students learn about human reflexes, how our bodies react to stimuli and how some body reactions and movements are controlled automatically, without thinking consciously about the movement or responses. In the associated activity, students explore how reflexes work in the human body by observing an involuntary human reflex and testing their own reaction times using dominant and non-dominant hands. Once students understand the stimulus-to-response framework components as a way to describe human reflexes and reactions in certain situations, they connect this knowledge to how robots can be programmed to conduct similar reactions.

GK-12 Program, Computational Neurobiology Center,

300

Human-Web Interactions  

NASA Astrophysics Data System (ADS)

Investigation of human behavior in electronic environments is rapidly gaining eminent position in web research. The driving forces of this endeavor originate from both commercial and scientific spheres. The commercial sector is eagerly exploring the human web behavior characteristics for amplifying and expanding the revenue generating possibilities. Novel trends in web development, as well as internet business models, unavoidably incorporate the elements of human-web interactions. The scientific inquiry into human web behavior is fundamentally oriented toward exploring, analyzing, understanding, modeling, and applying the findings.

Géczy, Peter; Izumi, Noriaki; Akaho, Shotaro; Hasida, Kôiti

301

Human Development Report 1997  

NSDL National Science Digital Library

The United Nations Development Programme's Human Development Report Office provides two useful selections from its Human Development Report 1997. Overview of HDR 1997 is a detailed summary of the contents of the report, discussing world poverty and a six point strategy for poverty reduction. HDR 1997 Rankings contain Human Development Index, Gender-Related Development Index and Gender Empowerment Measure rankings tables for 175 countries. More detailed information on the meaning of the HDI is contained in Analytical Tools for Human Development. Full text of the report is forthcoming, and ordering information is available at the site.

1997-01-01

302

The psychology of humanness.  

PubMed

This chapter explores the ways in which the concept of "humanness" illuminates a wide and fascinating variety of psychological phenomena. After introducing the concept--everyday understandings of what it is to be human--we present a model of the diverse ways in which humanness can be denied to people. According to this model people may be perceived as lacking uniquely human characteristics, and thus likened to animals, or as lacking human nature, and thus likened to inanimate objects. Both of these forms of dehumanization occur with varying degrees of subtlety, from the explicit uses of derogatory animal metaphors, to stereotypes that ascribe lesser humanness or simpler minds to particular groups, to nonconscious associations between certain humans and nonhumans. After reviewing research on dehumanization through the lens of our model we examine additional topics that the psychology of humanness clarifies, notably the perception of nonhuman animals and the objectification of women. Humanness emerges as a concept that runs an integrating thread through a variety of research literatures. PMID:23947277

Haslam, Nick; Loughnan, Steve; Holland, Elise

2013-01-01

303

Artificial human vision camera  

NASA Astrophysics Data System (ADS)

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.

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

2014-10-01

304

Human Research Tissues  

Cancer.gov

Frederick National Laboratory for Cancer Research Pathology Histotechnology Laboratory Request # Human Sample Biosafety FormIn addition to this form, please complete the Pathology / Histology Request.Contact

305

Human organ markets and inherent human dignity.  

PubMed

It has been suggested that human organs should be bought and sold on a regulated market as any other material property belongingto an individual. This would have the advantage of both addressing the grave shortage of organs available for transplantation and respecting the freedom of individuals to choose to do whatever they want with their body parts. The old arguments against such a market in human organs are, therefore, being brought back into question. The article examines the different arguments both in favour and against the sale of human organs. It concludes that the body and any of its elements is a full expression of the whole person. As such, they cannot have a price if the individual is to retain his or her full inherent dignity and if society is to retain and protect this very important concept. PMID:24979876

MacKellar, Calum

2014-01-01

306

Human Security Centre: Human Security Brief 2006  

NSDL National Science Digital Library

While the concept of human security is a relatively new one, there is a growing consensus that the subject is one that will continue to be of the utmost importance in the coming years. Generally, the term is used to describe "the complex of interrelated threats associated with civil war, genocide and the displacement of populations." Recently, the Human Security Centre (located at the University of British Columbia) published its annual Human Security Brief, and placed it online at this site. The report analyzes the findings of several datasets that track trends in such areas as organized violence against civilians and the conclusion of armed conflicts worldwide. While this ambitious work does have some positive findings to announce, there are a number of other troubling trends, such as the fact that four of the world's six regions have experienced increased numbers of conflicts since 2002.

307

Master of Human Resource Development Master of Human Resource Development  

E-print Network

1 Master of Human Resource Development Handbook Master of Human Resource Development Revised March, 2013 #12;2 Overview: The Master of Human Resource Development degree is designed for in - First Year HRD 830 Concepts of Human Resource Development 3 Credit Hrs. HRD 820 Human Performance

Duchowski, Andrew T.

308

Developing Human Resources through Actualizing Human Potential  

ERIC Educational Resources Information Center

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,…

Clarken, Rodney H.

2012-01-01

309

Health and Humanity: Humanities 401 Syllabus.  

ERIC Educational Resources Information Center

A syllabus for the "Health and Humanities" interdisciplinary course at Northwestern State University, Louisiana, is presented. An introduction suggests that with the proliferation of technological advances in the field of health care, there is a need for reconsideration of many moral, ethical, legal, and humanistic questions. Information is…

Snowden, Fraser; Taylor, Maxine

310

HUMAN DIGNITY AND HUMAN REPRODUCTIVE CLONING  

Microsoft Academic Search

he complexities and arguments both for and against human reproductive cloning (HRC) seem to have been discussed in almost every sphere imaginable. The worlds of law, medicine, science, bioethics, philosophy, and religion have all laid claim to the forum or framework in which the issues should be discussed. While public debate and the responses of national gov- ernments have been

Steven Malby

2002-01-01

311

Environment and the Humanities.  

ERIC Educational Resources Information Center

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)…

Allen, Rodney F., Ed.; And Others

312

The human genome project  

SciTech Connect

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 results of great significance.

Yager, T.D.; Zewert, T.E.; Hood, L.E. (California Institute of Technology, Pasadena, CA (United States))

1994-04-01

313

Introduction to human factors  

SciTech Connect

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)

Winters, J.M.

1988-03-01

314

integration division Human Systems  

E-print Network

situation awareness of vehicle operational state. 2. Quantify vibration effects on the usabilityintegration division Human Systems ISIS Vibration Test Facility Objective Approach Impact 1. Assess impact of flight-like whole-body vibration on human operational capabilities and ability to maintain

315

WORKPLACE VIOLENCE HUMAN RESOURCES  

E-print Network

WORKPLACE VIOLENCE HUMAN RESOURCES POLICY Human Resources | One Washington Square | San José, CA 95192-0046 | 408-924-2250 408-924-1701 (fax) SUBJECT: WORKPLACE VIOLENCE POLICY DATE: April 2008 that is free from intimidation, acts and/or threats of violence against life, health, well-being, and

Su, Xiao

316

Dynamics of Human Behavior  

Microsoft Academic Search

I review network aspects of human dynamics that link macro-historical to micro- sociological and evolutionary processes. The ability to bond in communities of varying spatial scales is a special property of humans that happens through social networks. These networks have greater cohesion through invulnerability to disconnection without removal of k nodes. Menger's (1927) connectivity theorem shows that this property of

Douglas R. White

317

Manage "Human Capital" Strategically  

ERIC Educational Resources Information Center

To strategically manage human capital in education means restructuring the entire human resource system so that schools not only recruit and retain smart and capable individuals, but also manage them in ways that support the strategic directions of the organization. These management practices must be aligned with a district's education improvement…

Odden, Allan

2011-01-01

318

Quantification of human responses  

NASA Technical Reports Server (NTRS)

Human perception is a complex phenomenon which is difficult to quantify with instruments. For this reason, large panels of people are often used to elicit and aggregate subjective judgments. Print quality, taste, smell, sound quality of a stereo system, softness, and grading Olympic divers and skaters are some examples of situations where subjective measurements or judgments are paramount. We usually express what is in our mind through language as a medium but languages are limited in available choices of vocabularies, and as a result, our verbalizations are only approximate expressions of what we really have in mind. For lack of better methods to quantify subjective judgments, it is customary to set up a numerical scale such as 1, 2, 3, 4, 5 or 1, 2, 3, ..., 9, 10 for characterizing human responses and subjective judgments with no valid justification except that these scales are easy to understand and convenient to use. But these numerical scales are arbitrary simplifications of the complex human mind; the human mind is not restricted to such simple numerical variations. In fact, human responses and subjective judgments are psychophysical phenomena that are fuzzy entities and therefore difficult to handle by conventional mathematics and probability theory. The fuzzy mathematical approach provides a more realistic insight into understanding and quantifying human responses. This paper presents a method for quantifying human responses and subjective judgments without assuming a pattern of linear or numerical variation for human responses. In particular, quantification and evaluation of linguistic judgments was investigated.

Steinlage, R. C.; Gantner, T. E.; Lim, P. Y. W.

1992-01-01

319

Immunology Taught by Humans  

PubMed Central

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

Davis, Mark M.

2013-01-01

320

Human Functional Brain Imaging  

E-print Network

Human Functional Brain Imaging 1990­2009 September 2011 Portfolio Review Summary Brain Imaging #12 Dale ­ one of our first Trustees. Understanding the brain remains one of our key strategic aims today three-fold: · to identify the key landmarks and influences on the human functional brain imaging

Rambaut, Andrew

321

Humanism within Globalization  

ERIC Educational Resources Information Center

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…

Weber, Jennifer E.

2014-01-01

322

Human Water Cycle  

NSDL National Science Digital Library

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.

Integrated Teaching and Learning Program,

323

Hooking Kids with Humanities.  

ERIC Educational Resources Information Center

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

Anstead, Neil L.

1993-01-01

324

Methods in human cytogenetics  

SciTech Connect

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.

NONE

1993-12-31

325

Human Adaptive Mechatronics  

Microsoft Academic Search

This article explains the background of human adaptive mechatronics (HAM) and the skill level of individuals to operate machines. It is natural to consider both human and environmental factors in the field of robotics and mechatronics. The progress of machines cannot be achieved without paying attention to these factors; a culture that accepts that this evolved through the contributions of

Satoshi Suzuki

2010-01-01

326

English and "Humanities"  

ERIC Educational Resources Information Center

Defends English instruction against the current trend of integrating such classes into humanities programs, arguing for the uniqueness and unpredictability of all experience and the human capacity to recreate, share, and evaluate experience as is taught in English. (Author/RB)

Lindley, David

1973-01-01

327

[Human ecology and hygiene].  

PubMed

Theoretical aspects of the human ecology, its place and significance in solution of biosphere protection problems are discussed. "Human ecology", "socioecology", interrelations of the terms with hygiene were also noted. Author supported the homocentric conception in the ecology problem aricing. Special attention was paid to the ecological education of physicians. PMID:1809648

Shepelin, O P

1991-11-01

328

Quantifying Human Performance Reliability.  

ERIC Educational Resources Information Center

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…

Askren, William B.; Regulinski, Thaddeus L.

329

Beliefs about Human Extinction  

SciTech Connect

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.

Tonn, Bruce Edward [ORNL

2009-11-01

330

Dogs catch human yawns.  

PubMed

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

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

2008-10-23

331

Studies of the binding of the magnesium-phosphoribosyl 1-pyrophosphate complex to orotate phosphoribosyltransferase from yeast  

SciTech Connect

Both C/sup 14/- and /sup 13/C-phosphoribosyl 1-pyrophosphate molecules, labeled at the C'-1 position, were synthesized biochemically with bacterial ribokinase and PRibPP synthetase activities. A flow dialysis experiment characterized the dissociation constant (33 ..mu..M) for the OPRTase-C/sup 14/PRibPP-Mg(II) complexation and defined 2 PRibPP binding sites per enzyme dimer. Moreover, labeled-PRibPP was observed to elute with a 50 ..mu..g sample of OPRTase through Sephadex Superfine G-25, suggesting that one form of the label is bound more tightly to the enzyme then the value of Kd would suggest. Samples of /sup 13/C-PRibPP, were characterized with /sup 13/C-NMR. A doublet appeared in the proton-decoupled PRibPP spectrum. The addition of a saturating level of Mg(II) to PRibPP resulted in a 0.1 ppm upfield shift. The addition of 0.6 mM OPRTase to a sample containing 0.9 mM /sup 13/C-PRibPP and 4 mM Mg (II) resulted in a disappearance of the doublet. Upon further addition of 1 mM /sup 13/C-PRibPP, four resonances were observed and tentatively assigned as follows: beta-/sup 13/C ribose 5' phosphate OPRTase bound-/sup 13/C-PRibPP, alpha-/sup 13/C-ribose 5' phosphate and a /sup 13/C-phosphoribosyl-OPRTase adduct. These assignments are consistent with the OPRTase ping pong kinetic mechanism, during which the pyrophosphate portion of PRibPP dissociates from the active site prior to orotate binding, and during which PRibPP undergoes hydrolysis within the time frame of the NMR experiment.

Ashton, R.W.; Sloan, D.L.

1987-05-01

332

Human Centric Computing School COMSC  

E-print Network

human activities and interactions when using traditional and pervasive computing systems. · Apply humanHuman 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

Martin, Ralph R.

333

Human Space Exploration  

NASA Technical Reports Server (NTRS)

The Mars probe, launched by India a few months ago, is on its way to Mars. At this juncture, it is appropriate to talk about the opportunities presented to us for the Human Exploration of Mars. I am planning to highlight some of the challenges to take humans to Mars, descend, land, stay, ascend and return home safely. The logistics of carrying the necessary accessories to stay at Mars will be delivered in multiple stages using robotic missions. The primary ingredients for human survival is air, water, food and shelter and the necessity to recycle the primary ingredients will be articulated. Humans have to travel beyond the van Allen radiation belt under microgravity condition during this inter-planetary travel for about 6 months minimum one way. The deconditioning of human system under microgravity conditions and protection of humans from Galactic cosmic radiation during the travel should be taken into consideration. The multi-disciplinary effort to keep the humans safe and functional during this journey will be addressed.

Jeevarajan, Antony

2014-01-01

334

Human fetal thyroid function.  

PubMed

The early steps of thyroid development that lead to its function in the human fetus and subsequently the further maturation that allows the human fetus to secrete thyroxine (T4) in a significant amount are reviewed here. We underline the importance of the transfer of T4 from the pregnant woman to her fetus, which contributes at all stages of the pregnancy to fetal thyroid function and development. In the first trimester of pregnancy, the temporal and structural correlation of thyroid hormone synthesis with folliculogenesis supported the concept that structural and functional maturations are closely related. Human thyroid terminal differentiation follows a precisely timed gene expression program. The crucial role of the sodium/iodine symporter for the onset of thyroid function in the human fetus is shown. Fetal T4 is detected by the eleventh week of gestation and progressively increases throughout. The pattern of thyroid hormones and thyroid-stimulating hormone levels in the course of pregnancy is given from fetal blood sampling data, and the mechanisms governing this maturation in the human fetus are discussed. Finally an example of primary human fetal thyroid dysfunction, such as in Down syndrome, is given. The understanding of the physiology of the human fetal thyroid function is the basis for fetal medicine in the field of thyroidology. PMID:25231441

Polak, Michel

2014-01-01

335

Archaea on Human Skin  

PubMed Central

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

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

2013-01-01

336

Human Plasma Protein C  

PubMed Central

Protein C is a vitamin K-dependent protein, which exists in bovine plasma as a precursor of a serine protease. In this study, protein C was isolated to homogeneity from human plasma by barium citrate adsorption and elution, ammonium sulfate fractionation, DEAE-Sephadex chromatography, dextran sulfate agarose chromatography, and preparative polyacrylamide gel electrophoresis. Human protein C (Mr = 62,000) contains 23% carbohydrate and is composed of a light chain (Mr = 21,000) and a heavy chain (Mr = 41,000) held together by a disulfide bond(s). The light chain has an amino-terminal sequence of Ala-Asn-Ser-Phe-Leu- and the heavy chain has an aminoterminal sequence of Asp-Pro-Glu-Asp-Gln. The residues that are identical to bovine protein C are underlined. Incubation of human protein C with human ?-thrombin at an enzyme to substrate weight ratio of 1:50 resulted in the formation of activated protein C, an enzyme with serine amidase activity. In the activation reaction, the apparent molecular weight of the heavy chain decreased from 41,000 to 40,000 as determined by gel electrophoresis in the presence of sodium dodecyl sulfate. No apparent change in the molecular weight of the light chain was observed in the activation process. The heavy chain of human activated protein C also contains the active-site serine residue as evidenced by its ability to react with radiolabeled diisopropyl fluorophosphate. Human activated protein C markedly prolongs the kaolin-cephalin clotting time of human plasma, but not that of bovine plasma. The amidolytic and anticoagulant activities of human activated protein C were completely obviated by prior incubation of the enzyme with diisopropyl fluorophosphate. These results indicate that human protein C, like its bovine counterpart, exists in plasma as a zymogen and is converted to a serine protease by limited proteolysis with attendant anticoagulant activity. Images PMID:468991

Kisiel, Walter

1979-01-01

337

Associate Vice President Human Resources  

E-print Network

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

Arnold, Jonathan

338

Human Resources Simon Fraser University  

E-print Network

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

Kavanagh, Karen L.

339

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

340

HUMAN SUBJECT PAYMENTS Policy Statement  

E-print Network

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

Shahriar, Selim

341

HUMAN GROSS ANATOMY ANTH 695  

E-print Network

1 HUMAN GROSS ANATOMY ANTH 695 THE UNIVERSITY OF TENNESSEE Instructor lectures: 33 ALUMNI MEMORIAL BUILDING Course description: Human Gross Anatomy knowledge) is also stressed. Course textbooks: Human gross anatomy uses four

Auerbach, Benjamin M.

342

UNDERGRADUATE STUDENT MANUAL HUMAN PHYSIOLOGY  

E-print Network

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

Guenther, Frank

343

UNDERGRADUATE STUDENT MANUAL HUMAN PHYSIOLOGY  

E-print Network

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

Guenther, Frank

344

The human genome project  

SciTech Connect

The Human Genome Project will obtain high-resolution genetic and physical maps of each human chromosome and, somewhat later, of the complete nucleotide sequence of the deoxyribonucleic acid (DNA) in a human cell. The talk will begin with an extended introduction to explain the Project to nonbiologists and to show that map construction and sequence determination require extensive computation in order to determine the correct order of the mapped entities and to provide estimates of uncertainty. Computational analysis of the sequence data will become an increasingly important part of the project, and some computational challenges are described. 5 refs.

Bell, G.I.

1991-06-01

345

Redrawing Humanity's Family Tree  

NSDL National Science Digital Library

This New York Times article details two skulls, one from central Africa and the other from the Black Sea republic of Georgia, that "have shaken the human family tree to its roots, sending scientists scrambling to see if their favorite theories are among the fallen fruit." The article discusses how the two skulls have caused scientists to rethink not only how we conceive of human evolution and its chain of events, but even the geography of evolution and migration patterns of very early humans.

Wilford, John N.

1969-12-31

346

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.

1998-01-01

347

Aluminium in human sweat.  

PubMed

It is of burgeoning importance that the human body burden of aluminium is understood and is measured. There are surprisingly few data to describe human excretion of systemic aluminium and almost no reliable data which relate to aluminium in sweat. We have measured the aluminium content of sweat in 20 healthy volunteers following mild exercise. The concentration of aluminium ranged from 329 to 5329?g/L. These data equate to a daily excretion of between 234 and 7192?g aluminium and they strongly suggest that perspiration is the major route of excretion of systemic aluminium in humans. PMID:24239230

Minshall, Clare; Nadal, Jodie; Exley, Christopher

2014-01-01

348

Human Computer Interaction  

NASA Astrophysics Data System (ADS)

The paper basically deals with the study of HCI (Human computer interaction) or BCI(Brain-Computer-Interfaces) Technology that can be used for capturing brain signals and translating them into commands that allow humans to control (just by thinking) devices such as computers, robots, rehabilitation technology and virtual reality environments. The HCI is based as a direct communication pathway between the brain and an external device. BCIs are often aimed at assisting, augmenting, or repairing human cognitive or sensory-motor functions.The paper also deals with many advantages of BCI Technology along with some of its applications and some major drawbacks.

Bhagwani, Akhilesh; Sengar, Chitransh; Talwaniper, Jyotsna; Sharma, Shaan

2012-08-01

349

Human dignity, humiliation, and torture.  

PubMed

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

Luban, David

2009-09-01

350

Teleoperator human factors study  

NASA Technical Reports Server (NTRS)

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

1984-01-01

351

Teleoperator human factors study  

NASA Technical Reports Server (NTRS)

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.

1984-01-01

352

Mapping of human chromosomes  

SciTech Connect

Chapter 31, is devoted to the mapping of human chromosomes. In 1990, a useful progress report appeared in the journal Science along with a beautiful wall chart of the Human Genome Map, which right now is only about 1% complete. The Human Genome Project launched by the National Institutes of Health and the Department of Energy aims at producing a complete sequence of the 3 x 10{sup 9} base pairs of DNA in the human genome within the next 15 years. This chapter describes identifying map sites, family studies, somatic cell genetics, chromosome rearrangements, other uses of deletions and translocations in mapping, in situ hybridization, and recombinant DNA gene mapping methods. 51 refs., 4 figs.

NONE

1993-12-31

353

Aerospace Human Factors  

NASA Technical Reports Server (NTRS)

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.

Jordan, Kevin

1999-01-01

354

What makes us human?  

E-print Network

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.

Mikkelsen, Tarjei S.

355

Teaching about Human Geography.  

ERIC Educational Resources Information Center

Presents a sampling of items from the ERIC database concerning the teaching of human geography. Includes documents dealing with Africa, Asia, the United States, Canada, Antarctica, and geographic concepts. Explains how to obtain ERIC documents. (SG)

Schlene, Vickie J.

1991-01-01

356

Approaches to Human Communication.  

ERIC Educational Resources Information Center

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…

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

357

Human Reliability Program Overview  

SciTech Connect

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.

Bodin, Michael

2012-09-25

358

Human teeth model  

NSDL National Science Digital Library

Humans are omnivores, meaning they eat both meat and plants. Omnivores generally have a mix of canines to shred meat and flat teeth to grind vegetation. The canines are less sharp than those seen in strict meat-eaters.

HÃ¥kan Svensson (None;)

2005-12-23

359

The Human Hazard.  

ERIC Educational Resources Information Center

Examines the plight of environmental refugees and the adequacy of political responses to the situation. Discusses the consequences of accelerated environmental change, particularly the impact of global warming on human migration. (LZ)

Tickell, Crispin

1995-01-01

360

Changes Affecting Human Interaction  

ERIC Educational Resources Information Center

Contemporary changes in population patterns, power structures, civil rights, and role adaptations, are affecting human interactions and self-concepts. These social changes call for a re-vamped educational system capable of contributing to a genuine community education. (JH)

Dodson, Dan W.

1970-01-01

361

Pushing Human Frontiers  

NASA Technical Reports Server (NTRS)

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.

Zubrin, Robert

2005-01-01

362

Human Assisted Assembly Processes  

SciTech Connect

Automatic assembly sequencing and visualization tools are valuable in determining the best assembly sequences, but without Human Factors and Figure Models (HFFMs) it is difficult to evaluate or visualize human interaction. In industry, accelerating technological advances and shorter market windows have forced companies to turn to an agile manufacturing paradigm. This trend has promoted computerized automation of product design and manufacturing processes, such as automated assembly planning. However, all automated assembly planning software tools assume that the individual components fly into their assembled configuration and generate what appear to be a perfectly valid operations, but in reality the operations cannot physically be carried out by a human. Similarly, human figure modeling algorithms may indicate that assembly operations are not feasible and consequently force design modifications; however, if they had the capability to quickly generate alternative assembly sequences, they might have identified a feasible solution. To solve this problem HFFMs must be integrated with automated assembly planning to allow engineers to verify that assembly operations are possible and to see ways to make the designs even better. Factories will very likely put humans and robots together in cooperative environments to meet the demands for customized products, for purposes including robotic and automated assembly. For robots to work harmoniously within an integrated environment with humans the robots must have cooperative operational skills. For example, in a human only environment, humans may tolerate collisions with one another if they did not cause much pain. This level of tolerance may or may not apply to robot-human environments. Humans expect that robots will be able to operate and navigate in their environments without collisions or interference. The ability to accomplish this is linked to the sensing capabilities available. Current work in the field of cooperative automation has shown the effectiveness of humans and machines directly interacting to perform tasks. To continue to advance this area of robotics, effective means need to be developed to allow natural ways for people to communicate and cooperate with robots just as they do with one another.

CALTON,TERRI L.; PETERS,RALPH R.

2000-01-01

363

Regulation of NAMPT in Human Gingival Fibroblasts and Biopsies  

PubMed Central

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

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

2014-01-01

364

Mapping the human genome  

SciTech Connect

This article is a review of the book Mapping the Human Genome: Using Law and Ethics as Guides, edited by George C. Annas and Sherman Elias. The book is a collection of essays on the subject of using ethics and laws as guides to justify human gene mapping. It addresses specific issues such problems related to eugenics, patents, insurance as well as broad issues such as the societal definitions of normality.

Annas, G.C.; Elias, S. (eds.)

1992-01-01

365

Human Bocavirus Infection, Canada  

Microsoft Academic Search

Human Bocavirus was detected in 18 (1.5%) of 1,209 respiratory specimens collected in 2003 and 2004 in Canada. The main symptoms of affected patients were cough (78%), fever (67%), and sore throat (44%). Nine patients were hospitalized; of these, 8 (89%) were <5 years of age. A new parvovirus, human Bocavirus (HBoV), was recently identified in Sweden (1). The virus

Nathalie Bastien; Ken Brandt; Kerry Dust; Diane Ward; Yan Li

2006-01-01

366

The human oncogenic viruses  

SciTech Connect

This book contains eight selections. The titles are: Cytogenetics of the Leukemias and Lymphomas; Cytogenetics of Solid Tumors: Renal Cell Carcinoma, Malignant Melanoma, Retinoblastoma, and Wilms' Tumor; Elucidation of a Normal Function for a Human Proto-Oncogene; Detection of HSV-2 Genes and Gene Products in Cervical Neoplasia; Papillomaviruses in Anogennital Neoplasms; Human Epstein-Barr Virus and Cancer; Hepatitis B Virus and Hepatocellular Carcinoma; and Kaposi's Sarcoma: Acquired Immunodeficiency Syndrome (AIDS) and Associated Viruses.

Luderer, A.A.; Weetall, H.H

1986-01-01

367

Human and Robot Sensors  

NSDL National Science Digital Library

Students are provided with a rigorous background in human "sensors" (including information on the main five senses, sensor anatomies, and nervous system process) and their engineering equivalents, setting the stage for three associated activities involving sound sensors on LEGO® robots. As they learn how robots receive input from sensors, transmit signals and make decisions about how to move, students reinforce their understanding of the human body's sensory process.

2014-09-18

368

Human–Bird Interactions  

Microsoft Academic Search

\\u000a The human–bird relationship is diverse and varies between cultures and within the same cultures over time. Humans have exploited\\u000a various avian species for millennia, using them for many different purposes including their flesh and eggs as food, skins\\u000a and feathers as clothing, egg shells and feathers (including whole taxidermied birds) as decorative items, feathers as quill\\u000a pens or as fletching

Patricia K. Anderson

369

Computers versus humans  

Microsoft Academic Search

The question is considered whether it is possibles@ humans to program computers that can mimic human mental activities. Vision as a perceptual process has been selectedj~r this purpose. In order to answer this question the conceptual model called E-B-C is proposed. In the E-B-C model E, B, and Care three observational points whose metaphorical meaning can be changed. From the

Milan E. Soklic

1998-01-01

370

Human exploration mission studies  

NASA Technical Reports Server (NTRS)

This paper describes several case studies of human space exploration, considered by the NASA's Office of Exploration in 1988. Special attention is given to the mission scenarios, the critical technology required in these expeditions, and the extraterrestrial power requirements of significant system elements. The cases examined include a manned expedition to Phobos, the inner Martian moon; a human expedition to Mars; the Lunar Observatory; and a lunar outpost to early Mars evolution.

Cataldo, Robert L.

1990-01-01

371

Geology and Human Health  

NSDL National Science Digital Library

This site contains a variety of educational and supporting materials for faculty teaching in the emerging field of geology and human health. You will find links to internet resources, books, teaching activities, and a group email list, as well as posters, presentations and discussions from the spring 2004 workshop on Geology and Human Health. These resources reflect the contributions of faculty members from across the country and the collections will continue to grow as materials are developed.

372

[Atypical human trypanosomoses].  

PubMed

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

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

2014-01-01

373

Human Factors Review Plan  

SciTech Connect

''Human Factors'' is concerned with the incorporation of human user considerations into a system in order to maximize human reliability and reduce errors. This Review Plan is intended to assist in the assessment of human factors conditions in existing DOE facilities. In addition to specifying assessment methodologies, the plan describes techniques for improving conditions which are found to not adequately support reliable human performance. The following topics are addressed: (1) selection of areas for review describes techniques for needs assessment to assist in selecting and prioritizing areas for review; (2) human factors engineering review is concerned with optimizing the interfaces between people and equipment and people and their work environment; (3) procedures review evaluates completeness and accuracy of procedures, as well as their usability and management; (4) organizational interface review is concerned with communication and coordination between all levels of an organization; and (5) training review evaluates training program criteria such as those involving: trainee selection, qualification of training staff, content and conduct of training, requalification training, and program management.

Paramore, B.; Peterson, L.R. (eds.)

1985-12-01

374

The human telomere  

SciTech Connect

An ultimate goal of human genetics is the generation of a complete physical and ''functional'' map of the human genome. Twenty-five percent of human DNA, however, consists of repetitive DNA sequences. These repetitive DNA sequences are thought to arise by many mechanisms, from direct sequence amplification by the unequal recombination of homologous DNA regions to the reverse flow of genetic information. A general outline of the chromosomal organization of these repetitive sequences will be discussed. Our working hypothesis is that certain classes of human repetitive DNA sequences ''encode'' the information necessary for defining long-range genomic structure. Evidence will be presented that the first goal of this research, the identification and cloning of the human telomere, has been achieved. A human repetitive DNA library was constructed from randomly sheared, reassociated, and oligo(G/center dot/C)-tailed DNA, a method that minimizes the potential loss of sequences devoid of a given restriction enzyme site. Sequences too large to clone efficiently in cosmid or /lambda/ vectors, such as centromeric repeats, or telomeric sequences with an end incompatible for cloning, should be present in this library. In order to isolate highly conserved repetitive DNA sequences, this library was screened with radiolabeled hamster Cot50 repetitive DNA. Two clones, containing tandem arrays of the sequence (TTAGGG), were isolated by this method. 30 refs., 1 fig., 2 tabs.

Moyzis, R.K.

1989-01-01

375

Immunogenetics of Human Placentation  

PubMed Central

Natural killer (NK) cells are a population of lymphocytes that function in both immune defense and reproduction. Diversifying NK cell phenotype and function are interactions between NK cell receptors and major histocompatibility complex (MHC) class I ligands. As a consequence of strong and variable selection these ligand-receptor systems are polymorphic, rapidly evolving, and considerably species-specific. Counterparts to the human system of HLA class I ligands and killer cell immunoglobulin-like receptors (KIR) are present only in apes and Old World monkeys. HLA-C, the dominant ligand for human KIR and the only polymorphic HLA class I expressed by trophoblast, is further restricted to humans and great apes. Even then, the human system appears qualitatively different from that of chimpanzees, in that it has evolved a genetic balance between particular groups of receptors and ligands that favor reproductive success and other groups of receptors and ligands that have been correlated with disordered placentation. Human populations that have survived successive episodes of epidemic disease and population bottlenecks maintain a breadth of diversity for KIR and HLA class I, implying that loss of such diversity disfavors long-term survival of a human population. PMID:22177321

Parham, Peter; Norman, Paul J.; Abi-Rached, Laurent; Hilton, Hugo G.; Guethlein, Lisbeth A.

2013-01-01

376

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;

377

HUMAN RESOURCE MANAGEMENT Human resource management is the process of  

E-print Network

5/2013 HUMAN RESOURCE MANAGEMENT Human resource management is the process of attracting the most. Human resource management professionals also design and oversee the use of performance appraisal systems environment. The Human Resource Management program at Wichita State University prepares you to meet

378

Science and the humanities: the case for state humanities councils  

Microsoft Academic Search

Although joined together by their commitment to inquiry, in their pursuit of seemingly divergent goals science and the humanities sometimes appear to be in tension. This article suggests that the public humanities programs sponsored by state humanities councils, the independent nonprofit state affiliates of the National Endowment for the Humanities, serve as vehicles for reconciling the differing concerns of science

G. M. Leftwich

2002-01-01

379

The Humanities and a Humanities Exploration Rodney Frey  

E-print Network

The Humanities and a Humanities Exploration Rodney Frey (from the keynote address given 12 September 2011) Now donning the regalia and dancing as the "distinguished humanities professorship" ­ though at my core still an ethnographer ­ this Humanities Exploration is really a year-long unfolding

O'Laughlin, Jay

380

College of Applied Human Sciences College of Applied Human Sciences  

E-print Network

Administration Health and Exercise Science Human Development and Family Studies Interior Design Nutrition Nutrition; Health and Exercise Science; Human Development and Family Studies; and Occupational TherapyCollege of Applied Human Sciences _______________ 2.6 Page 1 College of Applied Human Sciences

Stephens, Graeme L.

381

Human Pathogen Importation Importing "Human" Pathogens from Outside Canada  

E-print Network

Human Pathogen Importation Importing "Human" Pathogens from Outside Canada 1) Permits.gc.ca/ols-bsl/pathogen/index.html and scroll to the bottom of the page where you can download the "Application for Permit to Import Human Human Pathogens" and "CL2 Checklist" to PHAC at (613) 941-0596. There are no fees for this service. 5

382

The Human Condition: Medicine, Arts and Humanities Spring Quarter 2014  

E-print Network

The Human Condition: Medicine, Arts and Humanities INDE 212 Spring Quarter 2014 Thursdays from 2:15 to 4:05 This course is the Biomedical Ethics and Medical Humanities Scholarly Concentration gateway course for medical humanities. The course is open to all Stanford medical, graduate and undergraduate

Straight, Aaron

383

Policy on Human Subjects Research Policy on Human Subjects  

E-print Network

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

Sridhar, Srinivas

384

Infants' Responses to Real Humans and Representations of Humans  

ERIC Educational Resources Information Center

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…

Heron, Michelle; Slaughter, Virginia

2010-01-01

385

Humans in the Loop: Human-Computer Interaction and Security  

Microsoft Academic Search

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.

Sean W. Smith

2003-01-01

386

The state human trafficking and human rights issues in Africa  

Microsoft Academic Search

Internal factors in Africa which include limited autonomy of African states, the states’ various degrees of lack of capacity, as well as inept and parasitic leadership make human trafficking and human rights abuses in Africa inevitable. Regardless of the connections suggested to exist between globalization and human trafficking, internal factors in Africa are more fundamental than globalization in explaining human

Browne Onuoha

2011-01-01

387

Human Resource Development Bachelor of Science in Human Resource Development  

E-print Network

Human Resource Development Bachelor of Science in Human Resource Development FRESHMAN YEAR First in Human Resource Development (Fall only) 3 MGMT 309 Survey of Management 3 FINC 409 Survey of Finance. and Practices of Leadership in Human Resource Development 3 12 EHRD 491 Research 5,7 3 MKTG 409 Intro

Behmer, Spencer T.

388

Human capital accumulation: the role of human resource development  

Microsoft Academic Search

Introduces the special issue “Human resource development: sectoral and invention-level evidence of human capital accumulation”. Reviews the concepts and definitions of intellectual and human capital. Considers human capital from individual (employability, performance and career development) and organization (investment, ownership, skills and knowledge management) perspectives. Looks at each of the papers in the special issue, relating them to its theme. Highlights

Thomas N. Garavan; Michael Morley; Patrick Gunnigle; Eammon Collins

2001-01-01

389

The Human Genome From human genome to other  

E-print Network

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

Linial, Michal

390

Human behavior and human performance: Psychomotor demands  

NASA Technical Reports Server (NTRS)

The results of several experiments are presented in abstract form. These studies are critical for the interpretation and acceptance of flight based science to be conducted by the Behavior and Performance project. Some representative titles are as follow: External audio for IBM/PC compatible computers; A comparative assessment of psychomotor performance (target prediction by humans and macaques); Response path (a dependent measure for computer maze solving and other tasks); Behavioral asymmetries of psychomotor performance in Rhesus monkey (a dissociation between hand preference and skill); Testing primates with joystick based automated apparatus; and Environmental enrichment and performance assessment for ground or flight based research with primates;

1992-01-01

391

Meeting human needs  

NASA Technical Reports Server (NTRS)

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.

Nicogossian, Arnauld E.

1992-01-01

392

Spaceflight Human System Standards  

NASA Technical Reports Server (NTRS)

NASA created a new approach for human system integration and human performance standards. NASA created two documents a standard and a reference handbook. The standard is titled NASA Space Flight Human-System Standard (SFHSS) and consists of two-volumes: Volume 1- Crew Health This volume covers standards needed to support astronaut health (medical care, nutrition, sleep, exercise, etc.) Volume 2 Human Factors, Habitability and Environmental Health This volume covers the standards for system design that will maintain astronaut performance (ie., environmental factors, design of facilities, layout of workstations, and lighting requirements). It includes classic human factors requirements. The new standards document is written in terms so that it is applicable to a broad range of present and future NASA systems. The document states that all new programs prepare system-specific requirements that will meet the general standards. For example, the new standard does not specify a design should accommodate specific percentiles of a defined population. Rather, NASA-STD-3001, Volume 2 states that all programs shall prepare program-specific requirements that define the user population and their size ranges. The design shall then accommodate the full size range of those users. The companion reference handbook, Human Integration Design Handbook (HIDH), was developed to capture the design consideration information from NASA-STD-3000, and adds spaceflight lessons learned, gaps in knowledge, example solutions, and suggests research to further mature specific disciplines. The HIDH serves two major purposes: HIDH is the reference document for writing human factors requirements for specific systems. HIDH contains design guidance information that helps insure that designers create systems which safely and effectively accommodate the capabilities and limitations of space flight crews.

Holubec, Keith; Tillman, Barry; Connolly, Jan

2009-01-01

393

Human computing and machine understanding of human behavior: a survey  

Microsoft Academic Search

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

Maja Pantic; Alex Pentland; Anton Nijholt; Thomas S. Huang; F. Quek; Yie Yang

2006-01-01

394

Humanities Division UNIVERSITY OF OXFORD  

E-print Network

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

Oxford, University of

395

Humanities Division Janel Mueller, Dean  

E-print Network

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

He, Chuan

396

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 ...

397

Human evolution: taxonomy and paleobiology  

Microsoft Academic Search

This review begins by setting out the context and the scope of human evolution. Several classes of evidence, morphological, molecular, and genetic, support a particularly close relationship between modern humans and the species within the genus Pan, the chimpanzee. Thus human evolution is the study of the lineage, or clade, comprising species more closely related to modern humans than to

BERNARD WOOD; BRIAN G. RICHMOND

2000-01-01

398

Human Challenges in Exploration Missions  

NASA Technical Reports Server (NTRS)

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.

Lloyd, Charles W.

2007-01-01

399

Making IBM's Computer, Watson, Human  

ERIC Educational Resources Information Center

This essay uses the recent victory of an IBM computer (Watson) in the TV game, "Jeopardy," to speculate on the abilities Watson would need, in addition to those it has, to be human. The essay's basic premise is that to be human is to behave as humans behave and to function in society as humans function. Alternatives to this premise are considered…

Rachlin, Howard

2012-01-01

400

A Radioimmunoassay for Human Prolactin  

Microsoft Academic Search

A radioimmunoassay for primate prolactin has been developed, with [131I] monkey prolactin, and antibodies to monkey or human prolactin. The assay is specific for prolactin; human growth hormone, and human and monkey placental lactogen show no significant crossreaction. The assay is sensitive enough to measure prolactin concentrations in the sera of most humans studied. The concentration of prolactin in the

P. Hwang; H. Guyda; H. Friesen

1971-01-01

401

The Humanities at Triton College.  

ERIC Educational Resources Information Center

Designed to assist college personnel in assessing program needs, this report provides an overview of the humanities programs at Triton College. Part I focuses on curricular humanities programs, including discussions of the role and objectives of the School of Arts and Sciences; humanities courses offered in the school; special humanities…

Jacot, Robert E.; Prendergast, Nancy E.

402

Human dignity and human tissue: a meaningful ethical relationship?  

PubMed

Human dignity has long been used as a foundational principle in policy documents and ethical guidelines intended to govern various forms of biomedical research. Despite the vast amount of literature concerning human dignity and embryonic tissues, the majority of biomedical research uses non-embryonic human tissue. Therefore, this contribution addresses a notable lacuna in the literature: the relationship, if any, between human dignity and human tissue. This paper first elaborates a multidimensional understanding of human dignity that overcomes many of the shortcomings associated with the use of human dignity in other ethical debates. Second, it discusses the relationship between such an understanding of human dignity and 'non-embryonic' human tissue. Finally, it considers the implications of this relationship for biomedical research and practice involving human tissue. The contribution demonstrates that while human tissue cannot be said to have human dignity, human dignity is nevertheless implicated by human tissue, making what is done with human tissue and how it is done worthy of moral consideration. PMID:21478417

Kirchhoffer, David G; Dierickx, Kris

2011-09-01

403

Accessing naïve human pluripotency.  

PubMed

Pluripotency manifests during mammalian development through formation of the epiblast, founder tissue of the embryo proper. Rodent pluripotent stem cells can be considered as two distinct states: naïve and primed. Naïve pluripotent stem cell lines are distinguished from primed cells by self-renewal in response to LIF signaling and MEK/GSK3 inhibition (LIF/2i conditions) and two active X chromosomes in female cells. In rodent cells, the naïve pluripotent state may be accessed through at least three routes: explantation of the inner cell mass, somatic cell reprogramming by ectopic Oct4, Sox2, Klf4, and C-myc, and direct reversion of primed post-implantation-associated epiblast stem cells (EpiSCs). In contrast to their rodent counterparts, human embryonic stem cells and induced pluripotent stem cells more closely resemble rodent primed EpiSCs. A critical question is whether naïve human pluripotent stem cells with bona fide features of both a pluripotent state and naïve-specific features can be obtained. In this review, we outline current understanding of the differences between these pluripotent states in mice, new perspectives on the origins of naïve pluripotency in rodents, and recent attempts to apply the rodent paradigm to capture naïve pluripotency in human cells. Unraveling how to stably induce naïve pluripotency in human cells will influence the full realization of human pluripotent stem cell biology and medicine. PMID:22463982

De Los Angeles, Alejandro; Loh, Yuin-Han; Tesar, Paul J; Daley, George Q

2012-06-01

404

The Human Aerodynamic Wake  

NASA Astrophysics Data System (ADS)

The wake that trails behind a walking person in still air is, in effect, that of an irregular 3-D cylinder. At a brisk walking speed of 1.3 m/s (3 mph), the human wake is characterized by a Reynolds number of about 50,000. It is thus turbulent with underlying large-scale vortex motion. We show that buoyancy plays no role at this Reynolds number, even though it is dominant in the plume of a standing person. Computational Navier-Stokes solutions and laser-light-sheet experiments with a human subject reveal a large recirculation zone behind the torso and flow between the legs. The decay of a passive scalar introduced on the human body is found to be exponential with downstream distance. The volume flux in the human wake is roughly constant with downstream distance until the recirculation closes, whence it grows due to turbulent entrainment. Further experiments reveal the development of the wake from the human thermal plume as the Reynolds number (proportional to walking speed) is increased from zero to 50,000. These results pertain to the sensing of chemical traces in the wakes of walking persons for aviation security. Supported by FAA Grant 99-G-040.

Settles, Gary; Moyer, Zachary; Paterson, Eric; Edge, Brian

2003-11-01

405

The Human Serum Metabolome  

PubMed Central

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

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

406

Human HOX gene disorders.  

PubMed

The Hox genes are an evolutionarily conserved family of genes, which encode a class of important transcription factors that function in numerous developmental processes. Following their initial discovery, a substantial amount of information has been gained regarding the roles Hox genes play in various physiologic and pathologic processes. These processes range from a central role in anterior-posterior patterning of the developing embryo to roles in oncogenesis that are yet to be fully elucidated. In vertebrates there are a total of 39 Hox genes divided into 4 separate clusters. Of these, mutations in 10 Hox genes have been found to cause human disorders with significant variation in their inheritance patterns, penetrance, expressivity and mechanism of pathogenesis. This review aims to describe the various phenotypes caused by germline mutation in these 10 Hox genes that cause a human phenotype, with specific emphasis paid to the genotypic and phenotypic differences between allelic disorders. As clinical whole exome and genome sequencing is increasingly utilized in the future, we predict that additional Hox gene mutations will likely be identified to cause distinct human phenotypes. As the known human phenotypes closely resemble gene-specific murine models, we also review the homozygous loss-of-function mouse phenotypes for the 29 Hox genes without a known human disease. This review will aid clinicians in identifying and caring for patients affected with a known Hox gene disorder and help recognize the potential for novel mutations in patients with phenotypes informed by mouse knockout studies. PMID:24239177

Quinonez, Shane C; Innis, Jeffrey W

2014-01-01

407

Human herpesvirus 6.  

PubMed Central

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

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

1997-01-01

408

The Human Genome Program  

SciTech Connect

Early in 1986, Charles DeLisi, then head of the Office of Health and Environmental Research at the Department of Energy (DOE) requested the Los Alamos National Laboratory (LANL) to organize a workshop charged with inquiring whether the state of technology and potential payoffs in biological knowledge and medical practice were such as to justify an organized program to map and sequence the human genome. The DOE's interest arose from its mission to assess the effects of radiation and other products of energy generation on human health in general and genetic material in particular. The workshop concluded that the technology was ripe, the benefits would be great, and a national program should be promptly initiated. Later committees, reporting to DOE, to the NIH, to the Office of Technology Assessment of the US Congress, and to the National Academy of Science have reviewed these issues more deliberately and come to the same conclusion. As a consequence, there has been established in the United States, a Human Genome Program, with funding largely from the NIH and the DOE, as indicated in Table 1. Moreover, the Program has attracted international interest, and Great Britain, France, Italy, and the Soviet Union, among other countries, have been reported to be starting human genome initiatives. Coordination of these programs, clearly in the interests of each, remains to be worked out, although an international Human Genome Organization (HUGO) is considering such coordination. 5 refs., 1 fig., 2 tabs.

Bell, G.I.

1989-01-01

409

Geographic views of human development  

Microsoft Academic Search

Human development can be divided into three stages: human ancestors (Lower Palaeolithic), early human races (Middle Palaeolithic)\\u000a and modern humans (Upper Palaeolithic). Regional differentiation has been detected in the Lower Palaeolithic and is strongly\\u000a developed in the Middle Palaeolithic but continues into the Upper Palaeolithic less marked. Clearly mixture at all levels\\u000a accounts for this. Early humans absorbed the pre-existing

D. J. de Laubenfels

1995-01-01

410

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.

1998-01-01

411

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.

412

Telocytes in human oesophagus  

PubMed Central

Telocytes (TCs), a new type of interstitial cells, were identified in many different organs and tissues of mammalians and humans. In this study, we show the presence, in human oesophagus, of cells having the typical features of TCs in lamina propria of the mucosa, as well as in muscular layers. We used transmission electron microscopy (TEM), immunohistochemistry (IHC) and primary cell culture. Human oesophageal TCs present a small cell body with 2–3 very long Telopodes (Tps). Tps consist of an alternation of thin segments (podomers) and thick segments (podoms) and have a labyrinthine spatial arrangement. Tps establish close contacts (‘stromal synapses’) with other neighbouring cells (e.g. lymphocytes, macrophages). The ELISA testing of the supernatant of primary culture of TCs indicated that the concentrations of VEGF and EGF increased progressively. In conclusion, our study shows the existence of typical TCs at the level of oesophagus (mucosa, submucosa and muscular layer) and suggests their possible role in tissue repair. PMID:24188731

Chen, Xiaoke; Zheng, Yonghua; Manole, Catalin G; Wang, Xiangdong; Wang, Qun

2013-01-01

413

Is humanity suicidal?  

PubMed

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

Wilson, E O

1993-01-01

414

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"

415

Humanities on the Road  

NSDL National Science Digital Library

The goal of the Pennsylvania Humanities Council is to encourage lifelong learning, and one way they accomplish this goal is by sponsoring the Humanities on the Road. The show is an "arts and culture-themed television series showcas[ing] humanities presentations at cultural sites across Pennsylvania." The accompanying website provides visitors access to the episodes of the series, along with text about the content of each show. Visitors should check out the episode "May I Have the Pleasure of This Dance?", which was filmed at the Scranton Cultural Center at the Masonic Temple. A couple dances their way through history through waltzes, tangos, ragtime, and more. The "Behind the Scenes" tab near the top of the page offers visitors a glimpse into the world of the crew of the show, including interviews with the host, the series producer, the production assistant, and others.

416

Digital Humanities Tool Box  

NSDL National Science Digital Library

The Digital Humanities Tool Box, hosted on Scoop.It!, bills itself as a web site packed with âÂÂLinks, ideas, and tools for humanities instructors.â And thatâÂÂs exactly what it is. Curated by a history professor at Arizona State University (web name: Stillwater Humanities), the site âÂÂscoopsâ resources from around the web. Recent gems include articles like âÂÂHistoryâÂÂs Futureâ and âÂÂA Brief History of the Hashtag, and Other Unusual Punctuation Marks,â as well as infographics (for example, âÂÂ6 Ways Social Media Will Change in 2014âÂÂ) and blog entries (e.g. âÂÂWhat Digitization Will Do for the Future of MuseumsâÂÂ).

417

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.

418

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.

419

Antioxidants and human diseases.  

PubMed

Oxidative stress plays a pivotal role in the development of human diseases. Reactive oxygen species (ROS) that includes hydrogen peroxide, hyphochlorus acid, superoxide anion, singlet oxygen, lipid peroxides, hypochlorite and hydroxyl radical are involved in growth, differentiation, progression and death of the cell. They can react with membrane lipids, nucleic acids, proteins, enzymes and other small molecules. Low concentrations of ROS has an indispensable role in intracellular signalling and defence against pathogens, while, higher amounts of ROS play a role in number of human diseases, including arthritis, cancer, diabetes, atherosclerosis, ischemia, failures in immunity and endocrine functions. Antioxidants presumably act as safeguard against the accumulation of ROS and their elimination from the system. The aim of this review is to highlight advances in understanding of the ROS and also to summarize the detailed impact and involvement of antioxidants in selected human diseases. PMID:24933428

Rajendran, Peramaiyan; Nandakumar, Natarajan; Rengarajan, Thamaraiselvan; Palaniswami, Rajendran; Gnanadhas, Edwinoliver Nesamony; Lakshminarasaiah, Uppalapati; Gopas, Jacob; Nishigaki, Ikuo

2014-09-25

420

Human-Robot Interaction  

NASA Technical Reports Server (NTRS)

Risk of Inadequate Design of Human and Automation/Robotic Integration (HARI) is a new Human Research Program (HRP) risk. HRI is a research area that seeks to understand the complex relationship among variables that affect the way humans and robots work together to accomplish goals. The DRP addresses three major HRI study areas that will provide appropriate information for navigation guidance to a teleoperator of a robot system, and contribute to the closure of currently identified HRP gaps: (1) Overlays -- Use of overlays for teleoperation to augment the information available on the video feed (2) Camera views -- Type and arrangement of camera views for better task performance and awareness of surroundings (3) Command modalities -- Development of gesture and voice command vocabularies

Rochlis-Zumbado, Jennifer; Sandor, Aniko; Ezer, Neta

2012-01-01

421

Human exposure to aluminium.  

PubMed

Human activities have circumvented the efficient geochemical cycling of aluminium within the lithosphere and therewith opened a door, which was previously only ajar, onto the biotic cycle to instigate and promote the accumulation of aluminium in biota and especially humans. Neither these relatively recent activities nor the entry of aluminium into the living cycle are showing any signs of abating and it is thus now imperative that we understand as fully as possible how humans are exposed to aluminium and the future consequences of a burgeoning exposure and body burden. The aluminium age is upon us and there is now an urgent need to understand how to live safely and effectively with aluminium. PMID:23982047

Exley, Christopher

2013-10-01

422

Making Human Beings Human: Bioecological Perspectives on Human Development. The SAGE Program on Applied Developmental Science  

ERIC Educational Resources Information Center

To a greater extent than any other species, human beings create the environments that, in turn, shape their own development. This book endeavors to demonstrate that human beings can also develop those environments to optimize their most constructive genetic potentials. What makes human beings human, therefore, is both the potential to shape their…

Bronfenbrenner, Urie, Ed.

2004-01-01

423

Human mammary microenvironment better regulates the biology of human breast cancer in humanized mouse model.  

PubMed

During the past decades, many efforts have been made in mimicking the clinical progress of human cancer in mouse models. Previously, we developed a human breast tissue-derived (HB) mouse model. Theoretically, it may mimic the interactions between "species-specific" mammary microenvironment of human origin and human breast cancer cells. However, detailed evidences are absent. The present study (in vivo, cellular, and molecular experiments) was designed to explore the regulatory role of human mammary microenvironment in the progress of human breast cancer cells. Subcutaneous (SUB), mammary fat pad (MFP), and HB mouse models were developed for in vivo comparisons. Then, the orthotopic tumor masses from three different mouse models were collected for primary culture. Finally, the biology of primary cultured human breast cancer cells was compared by cellular and molecular experiments. Results of in vivo mouse models indicated that human breast cancer cells grew better in human mammary microenvironment. Cellular and molecular experiments confirmed that primary cultured human breast cancer cells from HB mouse model showed a better proliferative and anti-apoptotic biology than those from SUB to MFP mouse models. Meanwhile, primary cultured human breast cancer cells from HB mouse model also obtained the migratory and invasive biology for "species-specific" tissue metastasis to human tissues. Comprehensive analyses suggest that "species-specific" mammary microenvironment of human origin better regulates the biology of human breast cancer cells in our humanized mouse model of breast cancer, which is more consistent with the clinical progress of human breast cancer. PMID:25572806

Zheng, Ming-Jie; Wang, Jue; Xu, Lu; Zha, Xiao-Ming; Zhao, Yi; Ling, Li-Jun; Wang, Shui

2015-02-01

424

Augmented Human Engineering: A Theoretical and Experimental  

E-print Network

. Thus, augmented human design has to integrate human factors - anatomy, neurophysiology, behaviour12 Augmented Human Engineering: A Theoretical and Experimental Approach to Human Systems. Introduction This chapter focuses on one of the main issues for augmented human engineering: integrating

Paris-Sud XI, Université de

425

Human push capability.  

PubMed

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

Barnett, Ralph L; Liber, Theodore

2006-02-22

426

Defining the Human Microbiome  

PubMed Central

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

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

2012-01-01

427

Disorders of Human Hemoglobin  

NASA Astrophysics Data System (ADS)

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.

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

1980-02-01

428

Human MSH2 protein  

DOEpatents

The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error{sup +} (RER{sup +}) tumor cells. 19 figs.

Chapelle, A. de la; Vogelstein, B.; Kinzler, K.W.

1997-01-07

429

Human MSH2 protein  

DOEpatents

The human MSH2 gene, responsible for hereditary non-polyposis colorectal cancer, was identified by virtue of its homology to the MutS class of genes, which are involved in DNA mismatch repair. The sequence of cDNA clones of the human gene are provided, and the sequence of the gene can be used to demonstrate the existence of germ line mutations in hereditary non-polyposis colorectal cancer (HNPCC) kindreds, as well as in replication error.sup.+ (RER.sup.+) tumor cells.

de la Chapelle, Albert (Helsingfors, FI); Vogelstein, Bert (Baltimore, MD); Kinzler, Kenneth W. (Baltimore, MD)

1997-01-01

430

Mapping Human Epigenomes  

PubMed Central

As the second dimension to the genome, the epigenome contains key information specific to every type of cells. Thousands of human epigenome maps have been produced in recent years thanks to rapid development of high throughput epigenome mapping technologies. In this review, we discuss the current epigenome mapping toolkit and utilities of epigenome maps. We focus particularly on mapping of DNA methylation, chromatin modification state and chromatin structures, and emphasize the use of epigenome maps to delineate human gene regulatory sequences and developmental programs. We also provide a perspective on the progress of the epigenomics field and challenges ahead. PMID:24074860

Rivera, Chloe M.; Ren, Bing

2013-01-01

431

Ayahuasca and human destiny.  

PubMed

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

McKenna, Dennis J

2005-06-01

432

Sanitation and Human Health  

NSDL National Science Digital Library

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.

Science Netlinks

2000-12-06

433

[Controversies about human cloning].  

PubMed

Human cloning is one of the greatest scientific and research challenges that human kind faced so far. As much as we have reasons for excitement in front of achievements of the genetic engineering, also are great the fears about it. There is inevitable question: is the man aware where can cloning as an attack on a "natural laws for the life reproduction" can lead, or to say its impact on evolution diversities within kind that we belongs to. In this paper we have focus on finding the answer on the last question, with application of a multidisciplinary approach, which means not only scientific, but also ethical, as well as theology. PMID:16719236

Ziga, Jusuf

2006-01-01

434

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.

2008-07-31

435

Human Development Index Data  

NSDL National Science Digital Library

This data set traces the varying patterns of national progress in recent decades, documenting impressive long-term Human Development Index (HDI) gains even in most low-income countries. The data set also includes three innovative new measurements: the Inequality-adjusted Human Development Index (IHDI), the Gender Inequality Index (GII) and the Multidimensional Poverty Index (MPI). The data set is available in both CSV and SDMX file formats and contains more than 100 indicators that measure quality of life for all UN member states.

United Nations

436

Characteristics of human arm based on musculoskeletal model in human-human cooperative task  

Microsoft Academic Search

Human characteristics are supposed to be applied to the control systems of the human-friendly robots. Therefore, it is important to know the human characteristics in human-robot cooperative tasks. In this study, we considered a single rotational degree of freedom experimental system as well as a mass-spring-damper-friction dynamic model for the human arm and analyzed the master-slave and the master-semi master

Nan Zhang; Ryojun Ikeura; Yuanxin Wang; Kazuki Mizutani; Hideki Sawai

2007-01-01

437

Communicating with Virtual Humans.  

ERIC Educational Resources Information Center

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…

Thalmann, Nadia Magnenat

438

Human Papilloma Virus Infections  

PubMed Central

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

Wright, V. Cecil

1989-01-01

439

The human genome project.  

PubMed Central

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 in the present phase of the project. Advances in mapping techniques have allowed good progress toward the specific goals of the project and are also providing strong corollary benefits throughout biomedical research. Actual DNA sequencing of the genomes of the human and model organisms is still at an early stage. There has been little progress in the intrinsic efficiency of DNA-sequence determination. However, refinements in experimental protocols, instrumentation, and project management have made it practical to acquire sequence data on an enlarged scale. It is also increasingly apparent that DNA-sequence data provide a potent means of relating knowledge gained from the study of model organisms to human biology. There is as yet little indication that the infusion of technology from outside biology into the Human Genome Project has been effectively stimulated. Opportunities in this area remain large, posing substantial technical and policy challenges. PMID:8506271

Olson, M V

1993-01-01

440

Human genome I  

SciTech Connect

An international conference, Human Genome I, was held Oct. 2-4, 1989 in San Diego, Calif. Selected speakers discussed: Current Status of the Genome Project; Technique Innovations; Interesting regions; Applications; and Organization - Different Views of Current and Future Science and Procedures. Posters, consisting of 119 presentations, were displayed during the sessions. 119 were indexed for inclusion to the Energy Data Base.

Not Available

1989-01-01

441

The human genome project  

SciTech Connect

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 in the present phase of the project. Advances in mapping techniques have allowed good progress toward the specific goals of the project and are also providing strong corollary benefits throughout biomedical research. Actual DNA sequencing of the genomes of the human and model organisms is still at an early stage. There has been little progress in the intrinsic efficiency of DNA-sequence determination. However, refinements in experimental protocols, instrumentation, and project management have made it practical to acquire sequence data on an enlarged scale. It is also increasingly apparent that DNA-sequence data provide a potent means of relating knowledge gained from the study of model organisms to human biology. There is as yet little indication that the infusion of technology from outside biology into the Human Genome Project has been effectively stimulated. Opportunities in this area remain large, posing substantial technical and policy challenges. 80 refs.

Olson, M.V. (Univ. of Washington, Seattle (United States))

1993-05-15

442

Human Development Student Modules.  

ERIC Educational Resources Information Center

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…

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

443

Futures of Human Communication.  

ERIC Educational Resources Information Center

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…

Harms, L. S.

444

Structurally abnormal human autosomes  

SciTech Connect

Chapter 25, discusses structurally abnormal human autosomes. This discussion includes: structurally abnormal chromosomes, chromosomal polymorphisms, pericentric inversions, paracentric inversions, deletions or partial monosomies, cri du chat (cat cry) syndrome, ring chromosomes, insertions, duplication or pure partial trisomy and mosaicism. 71 refs., 8 figs.

NONE

1993-12-31

445

DIVISION OF HUMAN RESOURCES  

E-print Network

virus to co-workers or students. For more information regarding leave, refer to the Division of Human the potential for spreading the H1N1 flu virus to co-workers or students. For more information regarding leave and thoroughly with soap and warm water or use an alcohol-based hand sanitizer. Cover your mouth and nose when

Salama, Khaled

446

The Humanities, Unraveled  

ERIC Educational Resources Information Center

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…

Berube, Michael

2013-01-01

447

Human Social Genomics  

PubMed Central

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

Cole, Steven W.

2014-01-01

448

Medicine and the Humanities.  

ERIC Educational Resources Information Center

Discusses a Pennsylvania State University seminar program designed to help medical professionals explore aspects of medical treatment through readings in the humanities. Argues that the program is broader in vision and scope that other medical ethics courses. Suggests that the effort can refresh and deepen doctors' work with patients. (SG)

Pabst, Diana

1992-01-01

449

"Healthy" Human Development Indices  

ERIC Educational Resources Information Center

In the Human Development Index (HDI), life expectancy is the only indicator used in modeling the dimension "a long and healthy life". Whereas life expectancy is a direct measure of quantity of life, it is only an indirect measure of healthy years lived. In this paper we attempt to remedy this omission by introducing into the HDI the morbidity…

Engineer, Merwan; Roy, Nilanjana; Fink, Sari

2010-01-01

450

Comparing Humanities Instructors.  

ERIC Educational Resources Information Center

A nationwide survey was conducted of humanities and liberal arts instructors in spring 1983 to obtain information on instructors' age, ethnicity, degrees held, teaching experience, professional activities, goals, full-/part-time status, institutional support, and emphasis on various classroom activities. A comparison of survey results with…

Brawer, Florence B.

451

Energy and humanity  

Microsoft Academic Search

The era of cheap and abundant energy supplies has ended, and a radical change in the way of life is necessary if humanity is to be put first. This book attacks the problem of how, and to what extent, the increasing demand for energy can be met. The problem is presented as it exists now, with a view to what

M. W. Thring; R. J. Crookes

1974-01-01

452

Occupying the Digital Humanities  

ERIC Educational Resources Information Center

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…

Rice, Jeff

2013-01-01

453

The Classics as Humanities  

ERIC Educational Resources Information Center

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)

Norton, Mary E.

1975-01-01

454

HUMAN DEVELOPMENT GRADUATE GROUP  

E-print Network

Cognitive Focal Program 2 Socio-Emotional Focal Program 2 Family, Culture, and Society Focal Program 2 21 Fourth and Fifth Years 21 Summary Timetable 22 Graduate Studies Normative Time Rules 22 FINANCIAL Development Graduate Group is housed in the Division of Human Development and Family Studies (HDFS) within

Ullrich, Paul

455

Parochial altruism in humans  

Microsoft Academic Search

Social norms and the associated altruistic behaviours are decisive for the evolution of human cooperation and the maintenance of social order, and they affect family life, politics and economic interactions. However, as altruistic norm compliance and norm enforcement often emerge in the context of inter-group conflicts, they are likely to be shaped by parochialism-a preference for favouring the members of

Helen Bernhard; Urs Fischbacher; Ernst Fehr

2006-01-01

456

Marketing Human Resource Development.  

ERIC Educational Resources Information Center

Describes three human resource development activities: training, education, and development. Explains marketing from the practitioners's viewpoint in terms of customer orientation; external and internal marketing; and market analysis, research, strategy, and mix. Shows how to design, develop, and implement strategic marketing plans and identify…

Frank, Eric, Ed.

1994-01-01

457

Neurobiology and the Humanities  

PubMed Central

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

Zeki, Semir

2014-01-01

458

On Cloning Human Beings  

Microsoft Academic Search

The purpose of this paper is to show that arguments for and against cloning fail to make their case because of one or both of the following reasons: 1) they take for granted customary beliefs and assumptions that are far from being unquestionable; 2) they tend to ignore the context in which human cloning is developed. I will analyze some

Inmaculada de Melo-Martín

2002-01-01

459

HUMAN GENETICS Individualgenomesdiversify  

E-print Network

HUMAN GENETICS Individualgenomesdiversify Samuel Levy and Robert L. Strausberg The link between a person's genetic ancestry and the traits -- including disease risk -- that he or she exhibits remains. The rapid progress in genetic screening assays and DNA sequen- cing techniques promises to increase our

Zhang, Xin

460

Animating human athletics  

Microsoft Academic Search

This paper describes algorithms for the animation of men and women performing three dynamic athletic behaviors: running, bicycling, and vaulting. We animate these behaviors using control algorithms that cause a physically realistic model to perform the desired maneuver. For example, control algorithms allow the simulated humans to maintain balance while moving their arms, to run or bicycle at a variety

Jessica K. Hodgins; Wayne L. Wooten; David C. Brogan; James F. O'Brien

1995-01-01

461

Teleoperator human factors study  

NASA Technical Reports Server (NTRS)

The progress made on the Teleoperator Human Factors Study program during the period of September 7, 1985 to October 6, 1985 is discussed. Technical and programmatic problems that were encountered are discussed along with activity planned for the following month. The main portion of the report has been separated into four sections: Work Performed, Future Work, Problems Encountered, and Cost Information.

Bradford, K. Z.; Schappell, R. T.

1985-01-01

462

Human Memory: The Basics  

ERIC Educational Resources Information Center

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.

Martinez, Michael E.

2010-01-01

463

The human rete testis  

Microsoft Academic Search

The human rete testis was examined with regard to 1) the number and distribution of entrances of seminiferous tubules, 2) the light microscopic topography and 3) details of the passages as revealed by scanning and transmission electron microscopy. In a newborn 1474 entrances were counted, approximately 50 % entering from the right and 50 % from the left of the

E. C. Roosen-Runge; A. F. Holstein

1978-01-01

464

Human Learning and Memory  

ERIC Educational Resources Information Center

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…

Lieberman, David A.

2012-01-01

465

Designers of Human Settlements  

ERIC Educational Resources Information Center

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)

Cliff, Ursula

1976-01-01

466

Learning to Be Human  

ERIC Educational Resources Information Center

This article presents "Learning to be Human", which John Macmurray delivered on 5 May 1958 as the annual public lecture at Moray House College of Education, now part of Edinburgh University. The key themes of the paper are ones to which Macmurray returned again and again in both his educational and his philosophical writing for over 40 years and…

Macmurray, John

2012-01-01

467

Human Security Report Project  

NSDL National Science Digital Library

The Human Security Report Project (HSRP) is based at Simon Fraser University in Canada, and it "conducts research on global and regional trends in political violence, their causes and consequences and presents its findings in a manner that is accessible to the policy and research communities, the media, educators and the interested public." The "About" section states that the e-resources it provides through its website has effectively changed the way human security issues are understood and managed. The "Publications" link on the left hand side menu provides access to the "Human Security Brief" for 2005-2007, as well as to "Articles", "Books", "Book Chapters", "Workshop Reports" and "Opinion Pieces". The categories of data used in the HSRP are fleshed out in the "Data Resources" link on the left hand side of the page. The categories of data used are "Armed Conflict", "Deadly Assault on Civilians", "Terrorism", and "Other Human Security Indicators". The nine "Research Initiatives" of the HSRP can be accessed on the right hand side menu.

468

Human and information  

NASA Astrophysics Data System (ADS)

This is a lecture at the 15th anniversary of JICST Chugoku Branch Office. A recent progress of VLSI technologies will make possible to simulate some functions of human beings, the results of which will prepare next new innovation for a coming now century.

Mizuno, Hiroyuki

469

Glasgow Human Rights Network  

E-print Network

Human Rights Network, Kaleidoscope Trust and Pride Glasgow ­ and the conference steering group, we issues. www.gla.ac.uk/research/az/glasgowhumanrightsnetwork The Kaleidoscope Trust is a UK based charity.kaleidoscopetrust.com | facebook: kaleidoscopetrust | @Kaleidoscope_T Pride Glasgow is Glasgow and the West of Scotland's lesbian

Guo, Zaoyang

470

Humanities 1 Professor Edwards  

E-print Network

on human suffering and divine intervention (Odyssey 1.31-96) are incompatible." 2. Write a thesis in Sparta (Odyssey Bk 4 and 15.1-210), Homer makes it clear that Helen and Menelaus have put the hard in their debate (Odyssey 2.35- 163) because Antinous's arguments are rationally more compelling than those offered

Blanco, Philip R.

471

Human social genomics.  

PubMed

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

Cole, Steven W

2014-08-01

472

Potatoes and Human Health  

Microsoft Academic Search

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

Mary Ellen Camire; Stan Kubow; Danielle J. Donnelly

2009-01-01

473

Toward a Technical Humanism  

ERIC Educational Resources Information Center

Examines the relationship between education and development in developing nations. Advocates the fostering of a technical humanism--the development of knowledge in all its forms as a basis for action. In this system, technical education is as highly valued as general education. The system, and its applications to rural education is discussed. (CP)

Malassis, Louis

1977-01-01

474

Human hereditary hepatic porphyrias  

Microsoft Academic Search

The human hereditary hepatic porphyrias are diseases due to marked deficiencies of enzymes in the heme biosynthetic pathway. Porphyrias can be classified as either hepatic or erythroid, depending on the major production site of porphyrins or their precursors. The pathogenesis of inherited hepatic porphyrias has now been defined at the molecular level. Some gene carriers are vulnerable to a range

Yves Nordmann; Hervé Puy

2002-01-01

475

Biotechnologies and Human Dignity  

ERIC Educational Resources Information Center

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…

Sweet, William; Masciulli, Joseph

2011-01-01

476

Strength of Human Pulleys  

Microsoft Academic Search

The length, breaking strength, and tensile strength of each of the annular fibro-osseous pulleys of digital flexor sheath in ten fresh human cadaver specimens were measured. The first annular pulley and the fourth annular pulley were found to be the strongest, while the second annular pulley was the weakest. The design of artificial pulleys should reproduce the strength of the

PAUL R. MANSKE; PEGGY A. LESKER

1977-01-01

477

Animal and Human Communication.  

ERIC Educational Resources Information Center

Several misconceptions regarding the status of human communication systems relative to the systems of other animals are discussed in this paper. Arguments are offered supporting the expansion of the communication discipline to include the study of the communication systems of other species. The "communicative continuity" view which ranks man at…

Rummel, Lynda

478

Genital Human Papillomavirus Infection  

Microsoft Academic Search

Genital human papillomavirus (HPV) infection is a common sexually transmitted disease that at the present time is not effectively controlled or treated. Many infections are inapparent and transient. However, some HPV infections result in persistent lesions that in some cases undergo carcinogenic progression. A subset of genital HPVs, designated high-risk types, are preferentially associated with high-grade dysplasias and carcinomas. About

Douglas R. Lowy; Reinhard Kirnbauer; John T. Schiller

1994-01-01

479

Human Papillomavirus Infection  

Microsoft Academic Search

Condyloma acuminata, or genital warts, is the anogenital expression of human papillomavirus infection (HPV), and is the most common viral sexually transmitted disease (STD) in the United States. If subclinical infection is considered, it is many times more frequent than any other STD. Its rapidly increasing frequency, with an estimated increase in incidence of 459% from 1966 to 1981, 5

PAUL G. DYMENT

1996-01-01

480

Human-Robot Interaction  

NASA Technical Reports Server (NTRS)

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.

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

2015-01-01