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PubMed2000

Repair of oxidative DNA damage in Drosophila melanogaster: identification and characterization of dOgg1, a second DNA glycosylase activity for 8-hydroxyguanine and formamidopyrimidines.

In Drosophila, the S3 ribosomal protein has been shown to act as a DNA glycosylase/AP lyase capable of releasing 8-hydroxyguanine (8-OH-Gua) in damaged DNA. Here we describe a second Drosophila protein (dOgg1) with 8-OH-Gua and abasic (AP) site DNA repair activities. The Drosophila OGG1 gene codes for a protein of 327 amino acids, which shows 33 and 37% identity with the yeast and human Ogg1 proteins, respectively. The DNA glycosylase activity of purified dOgg1 was investigated using gamma-irradiated DNA and gas chromatography/isotope dilution mass spectrometry (GC/IDMS). The dOgg1 protein excises 8-OH-Gua and 2, 6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) from gamma-irradiated DNA. with k(ca)(t)/K:(M) values of 21.0 x 10(-5) and 11.2 x 10(-5) (min(-1) nM(-1)), respectively. Enzymatic assays using oligodeoxyribonucleotides containing a single lesion show that dOgg1 displays a marked preference for DNA duplexes containing 8-OH-Gua, 8-OH-Ade or an AP site placed opposite a cytosine. The cleavage of the 8-OH-Gua-containing strand results from the excision of the damaged base followed by a ss-elimination reaction at the 3'-side of the resulting AP site. Cleavage of 8-OH-Gua.C duplex involves the formation of a reaction intermediate that is converted into a stable covalent adduct in the presence of sodium borohydre. dOgg1 complements the mutator phenotype of fpg mutY mutants of Escherichia coli. Whole-mount in situ hybridizations on tissues at different stages of Drosophila development reveal that the dOGG1 messenger is expressed uniformly at a low level in cells in which mitotic division occurs. Therefore, Drosophila possesses two DNA glycosylase activities that can excise 8-OH-Gua and formamidopyrimidines from DNA, dOgg1 and the ribosomal protein S3.

Amino Acid Sequence↗

PubMed2003

Mononucleotide derivatives as ribosomal P-site substrates reveal an important contribution of the 2'-OH to activity.

The chemical synthesis of various acylaminoacylated mononucleotides is described and their activities as donor substrates for the ribosomal peptide synthesis were investigated using PhetRNA(Phe) as an acceptor. This minimal reaction was characterized in detail and was shown to be stimulated by CMP, cytidine and cytosine. By using several cytidine and cytosine analogs evidence is provided that this enhancement is rather caused by base pairing to rRNA, followed by a structural change, than by a base mediated general acid/base catalysis. Only derivatives of AMP proved active as P-site substrates. Further, a significant contribution of the 2'-OH to activity was indicated by the finding that AcLeu-dAMP was inactive as donor substrate, although it is a good inhibitor of peptide bond formation and thus, is presumably bound to the P-site. However, Di(AcLeu)-2'-OCH(3)-Ade and DiAcLeu-AMP were moderately active in this assay suggesting that the reactivity of the 3'-acylaminoacid ester is stimulated by the presence of the 2'-oxygen group. A model is discussed how further interactions of the 2'-OH in the transition state might influence peptidyl transferase activity.

Binding Sites↗

PubMed2006

Novel method for high throughput DNA methylation marker evaluation using PNA-probe library hybridization and MALDI-TOF detection.

The methylation of CpG dinucleotides has become a topic of great interest in cancer research, and the methylation of promoter regions of several tumor suppressor genes has been identified as a marker of tumorigenesis. Evaluation of DNA methylation markers in tumor tissue requires hundreds of samples, which must be analyzed quantitatively due to the heterogeneous composition of biological material. Therefore novel, fast and inexpensive methods for high throughput analysis are needed. Here we introduce a new assay based on peptide nucleic acid (PNA)-library hybridization and subsequent MALDI-TOF analysis. This method is multiplexable, allows the use of standard 384 well automated pipetting, and is more specific and flexible than established methods, such as microarrays and MS-SNuPE. The approach was used to evaluate three candidate colon cancer methylation markers previously identified in a microarray study. The methylation of the genes Ade-nomatous polyposis coli (APC), glycogen synthase kinase-beta-3 (GSK3beta) and eyes absent 4 (EYA4) was analyzed in 12 colon cancer and 12 normal tissues. APC and EYA4 were confirmed as being differentially methylated in colon cancer patients whereas GSK3beta did not show differential methylation.

Colorectal Neoplasms↗

PubMed2005

Benchmarking iron dextran sensitivity: reactions requiring resuscitative medication in incident and prevalent patients.

BACKGROUND: Reliable information on the incidence of severe reactions to iron dextran is limited. Administration of agents of resuscitation in acute anaphylaxis may serve as a marker to quantify life-threatening adverse drug reactions. METHODS: To determine the incidence of the most serious reactions to intravenous (i.v.) iron dextran, we searched the Gambro Healthcare US medical database for evidence of same-day administration of both i.v. iron dextran and parenteral adrenaline, corticosteroids or antihistamines. We confirmed each case as an iron dextran sensitivity reaction by direct inquiry. We also determined the total reported number of suspected adverse iron dextran reactions. RESULTS: During the 16 month study period, we determined that 1,066,099 doses of i.v. iron dextran were given to 48,509 patients, including 20,213 patients who had not previously received iron dextran (iron dextran naïve). We identified seven patients who experienced reactions requiring resuscitative agents, all in response to a test dose (five patients) or first therapeutic dose (two patients), and therefore all in the iron-naïve (incident) group. Thus, we found the incidence of iron dextran reactions requiring resuscitative agents to be 0.035% (7 out of 20,213). No reaction was fatal. In a combined group of incident and prevalent patients, we found 337 total reports of suspected adverse reactions to iron dextran, without regard to severity of reaction, yielding an overall per patient adverse drug event (ADE) rate of 0.69% (337 out of 48,509) and per exposure rate of 0.03% (337 out of 1,066,099). CONCLUSIONS: The incidence of reactions to iron dextran requiring resuscitative medications, per exposure or per patient, is approximately 0.035%. Reactions of this severity occur after either the test dose or first dose of iron dextran.

Adrenal Cortex Hormones↗

PubMed2005

Role of CYP2E1 in the epoxidation of acrylamide to glycidamide and formation of DNA and hemoglobin adducts.

Acrylamide (AA) is an animal carcinogen, neurotoxin, and reproductive toxin. AA is formed in baked and fried carbohydrate-rich foods. Metabolism of AA occurs via epoxidation to glycidamide (GA) or direct conjugation with glutathione. Using CYP2E1-null mice, recent studies in this laboratory demonstrated that induction of somatic and germ cell mutagenicity in AA-treated mice is dependent on CYP2E1. We hypothesized that AA metabolism to GA is a prerequisite for the induction of AA-induced mutagenicity. Current studies were undertaken to assess the role of CYP2E1 in the epoxidation of AA to GA and the formation of DNA and hemoglobin (HGB) adducts. AA was administered to CYP2E1-null or wild-type mice at 50 mg/kg ip. Mice were euthanized 6 h later and blood and tissues were collected. Using LC-ES/MS/MS, AA, GA, and DNA- and HGB-adducts were measured. While the plasma levels of AA and GA were 115 +/- 14.0 and 1.7 +/- 0.31 microM in CYP2E1-null mice, they were 0.84 +/- 0.80 and 33.0 +/- 6.3 microM in the plasma of AA-treated wild-type mice. Administration of AA to wild-type mice caused a large increase in N7-GA-Gua and N3-GA-Ade adducts in the liver, lung, and testes. While traces of N7-GA-Gua adducts were measured in the tissues of AA-treated CYP2E1-null mice, these levels were 52- to 66-fold lower than in wild-type mice. Significant elevation of both AA- and GA-HGB adducts was detected in AA-treated wild-type mice. In AA-treated CYP2E1-null mice, levels of AA-HGB adducts were roughly twice as high as those in wild-type mice. In conclusion, current work demonstrated that CYP2E1 is the primary enzyme responsible for the epoxidation of AA to GA, which leads to the formation of GA-DNA and HGB adducts.

Acrylamide↗

PubMed1988

Alpha adrenergic stimulation reduces cyclic adenosine 3',5'-monophosphate generation in rabbit myometrium by two mechanisms.

Rabbit myometrium contains postsynaptic alpha-1, alpha-2, and beta-2 adrenoreceptors. The response to endogenous catecholamines depends on the summation of interactions at these receptors and is influenced by the hormonal environment. Estrogen treatment of ovariectomized rabbits increases the alpha adrenergic contractile response whereas progesterone treatment of estrogen primed animals results in a predominance of the beta adrenergic response, which is inhibition of contractions. Of the receptor subtypes, only the alpha-2 receptor concentration is increased at physiological estrogen concentrations. However, alpha-2 receptors have not been shown to be directly involved in myometrial contraction, which appears to be mediated solely by alpha-1 adrenergic interactions. To test whether alpha-2 receptors might indirectly affect contraction by opposing interactions at the beta receptor, we examined the ability of alpha adrenergic stimulation to reduce myometrial cyclic adenosine 3',5'-monophosphate (cAMP) generation. We find that alpha-2 receptors inhibit myometrial ade adenylate cyclase through the guanine nucleotide regulatory protein, Gi. In addition, we find that activation of alpha-1 receptors also reduces cAMP generation. This interaction, which can be demonstrated in the absence but not the presence of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, does not appear to be mediated through Gi. These findings illustrate the complexity of adrenergic interactions in tissues containing several adrenergic subtypes.

1-Methyl-3-isobutylxanthine↗

PubMed2001

HIV incidence estimates among women of childbearing age in the area around Paris, France: no evidence for any effect of age or time.

OBJECTIVE: To explore whether there are any age or time effects on the HIV incidence rate among women of childbearing age in the area around Paris (France). DESIGN: Three seroprevalence surveys were conducted among pregnant women in the Paris area (PREVAGEST) during three periods (1990-1991, 1992-1993, 1994-1995); their data were used to derive HIV incidence estimates with Ades and Medley's method. To assess the power of our study, data were also simulated with a demographic model under different assumptions for HIV-incidence rates. RESULTS: No age or time effect was detected on HIV incidence in the Paris area during the period from 1990 to 1995. Analysis of simulated surveys showed that with the sample size of the PREVAGEST surveys, the method was able to detect an age or time effect with a relative risk of about 2.5 between age groups or periods. CONCLUSION: We conclude that the method is applicable to our data. If any existed, age or time effect was quite likely no higher than 2.5. As we previously reported using another method, incidence of HIV infection among women of childbearing age in the Paris area can be estimated at 0.74/1,000 per year (95% confidence interval, 0.62-0.87) from 1990 through 1995.

Adolescent↗

PubMed2002

A prospective study on fungal infection in children with cancer.

A prospective study was conducted in 1999 at the National Cancer Institute, Cairo University, to estimate the incidence, morbidity and mortality of fungal infections along with the evaluation of risk factors influencing outcome of infections among paediatric cancer patients. Of 1917 infectious episodes, the fungal infection rate as documented both clinically and microbiologically was 3.7% (70 cases). Fungal pathogens isolated were yeasts in 55 patients (78.6%) and moulds in 15 patients (21.11%). Among yeasts, Candida parapsilosis was the commonest, followed by C. tropicalis. Pneumonia was the most common fungal infection (n = 25, 35.7%), followed by fungaemia (n = 18, 25.7%). The overall mortality rate was 40% (n = 28), with an infection-related mortality of 28.5% (n = 20). Risk factors that accompanied mortality were relapsing or recurrent disease, profound neutropenia, ADE (Ara-C, daunorubocin and etoposide) protocol of chemotherapy, C. tropicalis isolated and fungaemia as a site of infection. Early use of empirical antifungal therapy (day 4) was not associated with a better outcome. In the light of the poor outcome of patients with fungaemia and fungal pneumonia, every effort should be made to prevent these infections in paediatric cancer patients.

Antifungal Agents↗

PubMed1978

Extension of a chromosome linkage group of Proteus mirabilis.

Mating procedures for detection of mobilization of the Proteus mirabilis chromosome were re-investigated. The chromosome was mobilized by plasmid D, the previously used hybrid between plasmids P-lac and R1drd19. About a 40-fold increase in recombinant recovery correlated with the absence of swarming during mating and a lower temperature of incubation. The modification introduced was that conjugation was allowed to proceed on a non-selective supplemented minimal medium at 30 degrees C before washing and plating on selective media. Final incubation was also at 30 degrees C. This technique enabled eight additional chromosomal markers to be mapped. Polarized transfer of the chromosome was shown by gradient of transmission experiments using a previously described marker as reference, by linkage analysis with reference to proximal and distal markers and (less successfully) by interrupted mating on solid medium. Markers of plasmid D transferred at high frequency to all recombinants. The plasmid was stable in recombinants and could transfer itself and chromosomal markers of the new hosts in further matings. Resulting recombination of markers occurred at usual frequencies. The marker order, his-1, ser-2, ura-2, pyrB1, trp-3, cysA1, ade-2, ilv-2, cysG1, gly-1, cysC1, argA2, metF2, nalA1, thr-1, leuB2, did not resemble the order of these markers in Escherichia coli.

Chromosome Mapping↗

PubMed1982

Secretion of tyrosinase in Streptomyces glaucescens.

In Streptomyces glaucescens, the intracellular and the extracellular enzyme forms of tyrosinase were found to be indentical in molecular weight (29 000), in copper content (0.21%), in the 19 amino acids at the amino-terminal end and in the ratio of cresolase to catecholase activity (0,005). The tyrosinase secretion process exhibited a constant rate of 0.15 units h-1 (mg protein)-1. Under highly induced conditions intracellular tyrosinase was accumulated. Mutations responsible for the non-melanogenic, tyrosinase-positive non-secretor mutant type are located chromosomally on the upper right arc of the S. glaucescens map near the ade-1 marker.

Catechol Oxidase↗

PubMed1996

Gene transfer and transposition mutagenesis in Streptomyces roseosporus: mapping of insertions that influence daptomycin or pigment production.

Streptomyces reseosporus, the producer of the cyclic lipopeptide antibiotic daptomycin, was shown to be a suitable host for molecular genetic manipulation. S. roseosporus does not appear to express significant restriction barriers based upon bacteriophage plaque formation studies. Plasmid DNA can be introduced into S. roseosporus by bacteriophage-FP43-mediated transduction and by conjugation from Escherichia coli. The streptomycete transposons Tn5096 and Tn5099, derived from IS493, transpose in S. roseosporus, and Tn5099-induced transposition mutants altered in the production of daptomycin, red pigment or black pigment were identified, and mapped to Dral and Asnl fragments. Three auxotrophic mutations (argB1, ade-1 and metB1) were identified among 100 individual Tn5096 insertions. Alignment and physical mapping of several Tn5099 insertions in Dral-E and Asnl-B fragments was facilitated by the presence of Dral and Asnl cleavage sites in Tn5099.

Bacteriophages↗

PubMed1975

Chromosome transfer in Proteus mirabilis mediated by hybrid plasmid.

A previously-described fused plasmid, P-lacRIdrd19, was found to mediate chromosomal transfer between cells of Proteus mirabilis strain PM5006; PM5006-(P-lacRIdrd19) was usually the donor and various auxotrophs of PM5006 resistant to nalidixic acid and/or streptomycin were recipients. The donor was usually counterselected with nalidixic acid and/or high concentrations of streptomycin. Recombination experiments with single markers indicated a 40-fold variation in recombination frequencies for different markers. Mapping double-auxotrophic markers by their gradient of transmission confirmed this variation and placed each of two independent isolates of eight markers in a linkage group his-ser-ura-pyrB-trp-cys-ade-ilv. Some donor markers did not register. Despite low recombination frequencies, interrupted mating experiments showed a polarity of early marker transfer. The segregation of unselected markers confirmed the order of some markers and showed that genetic material passed from the presumptive donor to the recipient. Recipients with two auxotrophic markers which could not be cotransduced by phage 5006M were converted to prototrophy by conjugation. The plasmid transferred to recipients at high frequency and all recombinants carried it. Recombinants could act as donors in further matings. Recombinants were fully susceptible to phage 5006M, unlike transductants of PM5006 by this phage. Direct involvement of the plasmid was indicated by drastically diminished recombination frequencies in crosses with recipients carrying P-lac as resident. P-lac had previously been shown to reduce the frequency of transfer of the hybrid plasmid to cells harbouring it. The histidine region was the first to register in recipients and recombined at the highest frequency of 5 times 10-6/donor cell. Some temporary association of plasmid and perhaps only the histidine region of the chromosome is favoured as the mechanism of chromosomal transfer. This could explain why not all donor markers could be mapped. Transduction and transformation were excluded as the cause of results.

Chromosome Mapping↗

PubMed1975

A plasmid involved in chloramphenicol production in Streptomyces venezuelae: evidence from genetic mapping.

To test the hypothesis that chloramphenicol production in Streptomyces venezuelae depends on the presence of a plasmid, mapping analysis was carried out by using eight markers in addition to chloramphenicol production and melanoid pigment formation. The sequence of the eight markers was determined on a circular linkage map as follows: -his-ade-str-leu-lys-met-ilv-pro-(his-). This sequence resulted in the frequency of quadruple crossover (q.c.o.) recombinants having the lowest value, 3-2 to 4-9%. However, the character of chloramphenicol non-production, which was obtained by incubating mycelia with acriflavin, was not required to explain the results. From these results and other tests, it is concluded that chloramphenicol production is controlled by a plasmid. This plasmid appeared to be non-transferable in conjugation.

Acriflavine↗

PubMed2000

A class of 6D conformal field theories: relation to 4D superconformal Yang-Mills theories?

We describe a class of six-dimensional conformal field theories that possibly are related to the tensionless string theories. They have an ADE classification, but no other discrete or continuous parameters, with the A(N-1) theory arising by factoring out the collective "center of mass" degrees of freedom from N noninteracting chiral two-forms. The Hilbert space carries an irreducible representation of the same Heisenberg group that appears in the tensionless string theories, and the "Wilson surface" observables obey the same superselection rules. When compactified on a two-torus, our theories have the same behavior under S duality as N = 4 super Yang-Mills theories.

Journal Article↗

PubMed2003

Quantum cosmology and conformal invariance.

According to Belinsky, Khalatnikov, and Lifshitz, gravity near a spacelike singularity reduces to a set of decoupled one-dimensional mechanical models at each point in space. We point out that these models fall into a class of conformal mechanical models first introduced by de Alfaro, Fubini, and Furlan (DFF). The deformation used by DFF to render the spectrum discrete corresponds to a negative cosmological constant. The wave function of the Universe is the zero-energy eigenmode of the Hamiltonian, or the spherical vector of the representation of the conformal group SO(1,2). A new class of conformal quantum mechanical models with enhanced ADE symmetry is constructed, based on the quantization of nilpotent coadjoint orbits.

Journal Article↗

PubMed1975

Comparative Activity of Isomers of Zeatin and Ribosyl-Zeatin on Funaria hygrometrica.

The activities of isomers of zeatin, ribosyl-zeatin, and 6-(gamma,gamma-dimethylallylamino) purine (i(6)Ade) on the moss Funaria hygrometrica are compared by measuring the ability of the cytokinins to induce callus or gametophores. The cis- and trans-ribosyl-zeatins were inactive, and therefore this kind of bioassay cannot be used as evidence for the presence or absence of a cytokinin in tests on natural products.

Journal Article↗

PubMed1976

Cytokinins in Corynebacterium fascians Cultures: Isolation and Identification of 6-(4-Hydroxy-3-methyl-cis-2-butenylamino)-2-methylthiopurine.

In addition to the four cytokinins, 6-(3-methyl-2-butenylamino)purine, 6-methylaminopurine and the cis and trans isomers of 6-(4-hydroxy-3-methyl-2-butenylamino)purine, reported earlier from our laboratories, three cytokinin-active fractions have been obtained from the aqueous medium of 6-day-old Corynebacterium fascians cultures. One of these has been identified as 6-(4-hydroxy-3-methyl-cis-2-butenylamino)-2-methylthiopurine (2-methylthio-cis-zeatin, c-ms(2)io(6) Ade).The elution volumes of the other two fractions correspond to those of authentic 6-(4-hydroxy-3-methyl-2-butenylamino)-9-beta-d-ribofuranosyl-purine and 6-(3-methyl-2-butenylamino)-9-beta-d-ribofuranosylpurine, indicating the presence of trace amounts of these two ribonucleosides.

Journal Article↗

PubMed1989

Kinetic comparison of cytokinin nucleosidase activity isolated from normally ripening and mutant tomato varieties.

Kinetic parameters for cytokinin nucleosidase activity which catalyzes the deribosylation of N(6)(Delta(2)-isopentenyl)adenosine (I(6)Ado) to produce the more "active" free base N(5)(Delta(2)-isopenetyl)adenine (I(6)Ade) were compared for a normally ripening tomato (Lycopersicon esculentum L.) cultivar Rutgers, and two mutant tomato varieties (Nor and Rin). K(m) for nucleosidase activity in Rutgers was lower (K(m) = 0.1 millimolar) than that in either Nor (K(m) = 0.14 millimolar) or Rin (K(m) = 0.13 millimolar).

Journal Article↗