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PubMed1986

Modifiers of mutation rate: a general reduction principle.

A deterministic two-locus population genetic model with random mating is studied. The first locus, with two alleles, is subject to mutation and arbitrary viability selection. The second locus, with an arbitrary number of alleles, controls the mutation at the first locus. A class of viability-analogous Hardy-Weinberg equilibria is analyzed in which the selected gene and the modifier locus are in linkage equilibrium. It is shown that at these equilibria a reduction principle for the success of new mutation-modifying alleles is valid. A new allele at the modifier locus succeeds if its marginal average mutation rate is less than the mean mutation rate of the resident modifier allele evaluated at the equilibrium. Internal stability properties of these equilibria are also described.

Alleles↗
PubMed1980

Host age and H-2 tolerance in chimeric mice: mixed lymphocyte reactivity, cell-mediated lympholysis and responses to hapten-modified self.

In order to further our understanding of the reasons for the increased susceptibility of aged animals to autoimmunity, neoplasms and infectious diseases, experiments were performed to determine the ability of an aged environment to induce and support tolerance to major histocompatibility complex (MHC) determinants as well as to support the development of a specific immune response to modified self-determinants. The degree and mechanisms of tolerance to host and donor histocompatibility antigens were studied in bone marrow chimeras of the type (C57B1/6 X CBA)F1 leads to (C57B1/6 X DBA/2)F1 (BCF1 and BDF1, respectively). BCF1 bone marrow donors were 6 weeks old and BDF1 hosts were 18 months old at the time of chimerization. Four to ten months later, chimeras were found to fully tolerant to all three parental haplotyes and competent to respond to fourth-party strains as assessed in both mixed lymphocyte reactions and cell-mediated lympholysis. Tolerance to parental haplotypes could not be attributed to active suppression of reactivity. The aged host environment proved incapable of supporting the development of anti-modified self-reactivity as attested by the fact that neither the senescent BDF1 mice nor the BCF1 leads to BDF1 chimeras established in aged hosts could respond to trinitrophenol-modified autologous parental cells. In contrast, young BDF1 mice and BCF 1 leads to BDF1 chimeras established in young adult hosts were competent to respond to trinitrophenol-modified autologous and parental cells in an MHC restricted fashion. The significance of these results to the susceptibility of aged animals to intracellular parasitic infections and neoplasia is discussed.

Aging↗
PubMed1985

Polyethylene glycol-modified ragweed pollen extract in rhinoconjunctivitis.

Sixty-two ragweed-sensitive adult subjects volunteered to take part in a 2-year, placebo-controlled efficacy study of polyethylene glycol (PEG)-modified ragweed extract, in ragweed pollen-induced rhinoconjunctivitis. At the beginning of the study, subjects were stratified according to skin sensitivity to ragweed extract and PEG-modified ragweed and the severity of hay fever in the previous year. There was random allocation of half to active treatment and half to placebo treatment. Before the first ragweed pollen season the 36 most sensitive subjects received 10 weekly injections (group 1), and the remaining 26 received six injections (group 2). Before the second season all subjects received 10 injections. Doses increased by half a log concentration each week unless there were adverse reactions. The mean total dose received by group 1 in year 1 was 385 micrograms of protein (28.9 micrograms AgE) and received by group 2 was 218 micrograms of protein (16.4 micrograms AgE). In year 2 the mean total dose was 1829 micrograms (137.2 micrograms AgE). Sixty-six percent of injections elicited no reaction or a mild local reaction; the remaining injections produced local redness and swelling more than 2 inches in diameter. Four percent of injections produced systemic symptoms. PEG-modified ragweed stimulated increases in ragweed specific IgG antibody both years, but increases in ragweed specific IgE antibody were significant only in group 1 in year 1. The magnitude of the IgG antibody changes was directly related to the total dose injected. At the beginning of the second year, PEG-modified ragweed-treated subjects still had elevated IgG antibody levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse.

Mutations in the human APC gene caused various familial colon cancer syndromes. The Multiple intestinal neoplasia (Min) mouse provides an excellent model for familial colon cancer: it carries a mutant mouse Apc gene and develops many intestinal adenomas. Here, we analyze how this tumor phenotype is dramatically modified by genetic background. We report the genetic mapping of a locus that strongly modifies tumor number in Min/+ animals. This gene, Mom-1 (Modifier of Min-1), maps to distal chromosome 4 and controls about 50% of genetic variation in tumor number in two intraspecific backcrosses. The mapping is supported by a LOD score exceeding 14. Interestingly, Mom-1 lies in a region of synteny conservation with human chromosome 1p35-36, a region of frequent somatic loss of heterozygosity in a variety of human tumors, including colon tumors. These results provide evidence of a major modifier affecting expression of an inherited cancer syndrome.

Adenomatous Polyposis Coli↗
PubMed1995

Resin-modified glass ionomers for luting posterior ceramic restorations.

OBJECTIVES: Until recently, esthetic inlay restorations in posterior teeth have been limited to cavities surrounded by enamel. Dentin adhesive systems in combination with luting composites and light-cured resin-modified glass ionomer cements offer a possibility for bonding ceramic inlays to cavities when the cervical margin is in dentin. This study was designed to compare in vitro marginal integrity of ceramic inlays bonded to dentin to restorations placed in cavities with margins located entirely in the enamel. METHODS: In the present in vitro study, the sealing abilities of a dentin bonding agent/luting composite combination (Syntac/Dual Cement, Vivadent) and resin-modified glass ionomers (Photac Fil, Photac Bond, ESPE; Dyract, De Trey Dentsply; Fuji II LC, GC Dental Industrial Corp.; and Vitremer, 3M Dental Products) used as luting agents in cavities extending beyond the cemento-enamel junction, were compared to the sealing abilities of a conventional luting composite (Vita Cerec Duo Cement, Vita) in cavities within sound enamel. SEM analysis and dye penetration were performed to evaluate marginal integrity at the cervical cavity margins. RESULTS: The dentin bonding agent/luting composite combination (Syntac/Dual Cement) rendered a marginal seal within the dentin similar to the quality obtained with the conventional luting procedures within sound enamel. When three out of the five resin-modified glass ionomers were used as luting agents (Dyract, Fuji II LC and Vitremer), the results were comparable to those reported for the dentin bonding agents and the conventional method. SIGNIFICANCE: Light-cured resin-modified glass ionomer cements may be considered as an alternative to dentin bonding agents when the cavity margins of ceramic inlay restorations are within the dentin. However, further studies, e.g., wear resistance, must be performed.

Bicuspid↗
PubMed1995

Curing shrinkage and volumetric changes of resin-modified glass ionomer restorative materials.

OBJECTIVES: The objective of the study was to evaluate initial curing shrinkage and volumetric change during water storage of six resin-modified glass ionomer cements (Dyract, DeTrey Dentsply; Fuji II LC, GC Dental Int.; Ionosit Fil, DMG; VariGlass VLC, DeTrey Dentsply; Vitremer, 3M Dental Products; Photac-Fil, ESPE), a hybrid composite (blend-a-lux, Blendax) and a chemical-cured glass ionomer cement (ChemFil Superior, DeTrey Dentsply). METHODS: The curing shrinkage was determined 5 min and 24 h after polymerization and mixing, respectively. Volumetric changes were examined after 14 d and 28 d water storage. Curing shrinkage and volumetric changes were evaluated using the hydrostatic principle. In addition, the total water content of the materials was measured after 28 d water storage. RESULTS: Curing shrinkage of most of the resin-modified glass ionomers was greater than the hybrid composite and the chemical-cured glass ionomer cement. After a 28 d water storage, the resin-modified glass ionomers showed volumetric expansion and the chemical-cured glass ionomer showed volumetric loss. All of the examined glass ionomer materials had a higher total water content than the composite. SIGNIFICANCE. The large curing shrinkage of the resin-modified glass ionomer materials measured in this in vitro study could affect the marginal integrity of glass ionomer restorations.

Acrylic Resins↗
PubMed1992

Tissue response to intraperitoneal implants of polyethylene oxide-modified polyethylene terephthalate.

Polyethylene terephthalate films surface modified with polyethylene oxide of mol wt 18,500 g/mol (18.5 k) by a previously described technique, were implanted in the peritoneal cavity of mice, along with their respective untreated controls, for periods of 1-28 d. The implants were retrieved and examined for tissue reactivity and cellular adherence. The control polyethylene terephthalate surfaces showed an initial inflammatory reaction followed by an extensive fibrotic response with a mean thickness of 60 microns at 28 d. By contrast, polyethylene oxide-modified polyethylene terephthalate showed only a mild inflammatory response and no fibrotic encapsulation throughout the implantation period: at 28 d a cellular monolayer was observed. Apparently either the polyethylene oxide-modified surface was stimulating less inflammation, which was in turn stimulating less fibroblastic overgrowth, or the cellular adhesion to the polyethylene oxide-modified surface was too weak to support cellular multilayers.

Animals↗
PubMed1992

In vitro leucocyte adhesion to modified polyurethane surfaces. I. Effect of ionizable functional groups.

To study the effect of ionizable functional groups on the adhesion of leucocytes to surfaces, both poly(ethyleneimine) and poly(acrylic acid) were immobilized on polyurethane films, resulting in the introduction of amine and carboxylic acid groups, respectively. This was confirmed by contact angle measurements and XPS analysis. In vitro adhesion of granulocytes and lymphocytes on untreated and modified surfaces was compared. The number of adherent cells on modified surfaces as a function of time was significantly higher than on untreated surfaces. This effect was most pronounced for the adhesion of lymphocytes to surfaces modified with amine groups. In this case, the number of adherent cells after 1 h of exposure was three times higher than on untreated surfaces. A moderate enhancement of leucocyte adhesion was observed in the case of surfaces modified with carboxylic acid groups. There is evidence that these groups were not ionized under the experimental conditions used. The modification procedures described may be used to improve polyurethane filters for the removal of leucocytes from blood.

Cell Adhesion↗
PubMed1993

ppHEMA-modified silicone rubber film towards improving rabbit corneal epithelial cell attachment and growth.

A plasma polymerized HEMA (ppHEMA) film was prepared by plasma deposition polymerization onto an elastic material, silicone rubber. The surfaces of control, argon plasma-treated, and ppHEMA-modified silicone rubber were characterized by ESCA, FTIR-ATR and SEM techniques. ESCA verified the respective chemical shift of control and ppHEMA-modified films. The presence of the ppHEMA was also verified by ESCA. The introduction of ppHEMA onto a hydrophobic support provided an adequate surface for rabbit corneal epithelial cell attachment and growth. Cell attachment and growth onto these surfaces were examined by light microscopy. Cell attachment onto the control and the argon plasma-treated surface was negligible, while improved attachment and growth of rabbit corneal epithelium cells was demonstrated on the ppHEMA-modified polymeric surface. The ppHEMA-modified silicone rubber surface demonstrated a confluent cell layer after 72 h.

Animals↗
PubMed1996

In vitro investigation of fluoride ion release from four resin-modified glass polyalkenoate cements.

Conventional glass ionomer cements are known to release fluoride ions to the surroundings. Recently, resin-modified glass ionomer cements have been produced. These have differing chemical formulations and this may affect their ability to release fluoride ions. The study evaluates both the fluoride release and compressive strength of one conventional and four resin-modified glass ionomer cements with respect to time. The results showed that the formulation of the resin-modified materials influenced the fluoride release. One resin-modified glass ionomer (PhotacFil) released more fluoride than all other materials, while Vitremer, Fuji II LC and Chemfil Superior release similar amounts. Variglass had a very much smaller elution of fluoride ions. This suggests that there is considerable variation in fluoride release between materials of similar generic origin. The compressive strength of these materials was not affected with time.

Biocompatible Materials↗
PubMed1988

The use of rat urine extracted on XAD-2 resin and assayed in a microsuspension-modified Ames test as an in vivo indicator of genotoxic exposure.

The measurement of urinary mutagenicity is a non-invasive monitoring tool which often reflects an animal's recent exposure to genotoxic agents. Although studies in man are indispensable for monitoring industrial and/or environmental exposure to genotoxins, a sensitive laboratory animal model is necessary for mechanistic studies on the role of specific chemical exposure in altering urinary mutagenicity. The objective of this study was to enhance the sensitivity of the methodology used for detecting urinary mutagenicity in rats by using XAD-2 resin to extract and concentrate the urine and a microsuspension-modified Ames test to quantify mutagenicity. The polycyclic aromatic hydrocarbon benzo[a]pyrene (BP) and the aromatic amine 2-acetylaminofluorene (AAF) were used as test compounds. Under the conditions of our study, AAF administered to rats by gavage at doses of 1 mg/kg or higher induced a dose-dependent increase in urine mutagenicity. The greatest mutagenic response was seen when S9 was present during the microsuspension-modified Ames test and beta-glucuronidase (BG) was not included. Similarly, BP administered to rats by gavage at doses of 10 mg/kg or higher induced a dose-dependent increase in urinary mutagenicity. The relative importance of BG and S9 were quite different with BP than with AAF. With BP, mutagenicity was greatest when both S9 and BG were present during the microsuspension-modified Ames test, and least with S9 and without BG. In both AAF- and BP-treated animals, extraction of the urine on XAD-2 resin markedly enhanced the mutagenic response compared to neat urine, but partitioning of the XAD-2 eluate into methylene chloride always diminished the mutagenicity of the urine extract. The results demonstrate the sensitivity and reproducibility of rodent urinary mutagenicity assays when XAD-2 resin is used to extract and concentrate the urine and a microsuspension-modified Ames test is used to quantify mutagenicity. This sensitive method should facilitate mechanistic studies on the roles of specific environmental agents in affecting urinary mutagenicity and, in addition, may be used during acute, subchronic and chronic rodent bioassays as a non-invasive in vivo indicator of genotoxic exposure.

2-Acetylaminofluorene↗
PubMed1991

Tea tannin components modify the induction of sister-chromatid exchanges and chromosome aberrations in mutagen-treated cultured mammalian cells and mice.

The modifying effects of tannin components extracted from green tea and black tea on mutagen-induced SCEs and chromosome aberrations were studied. These tannin components did not affect spontaneous SCEs and chromosome aberrations in cultured Chinese hamster cells. The frequency of SCEs and chromosome aberrations induced by mitomycin C (MMC) or UV was enhanced by the posttreatment with tea tannin components. When cells were post-treated with tea tannin components in the presence of metabolic enzymes of rat liver (S9 mix), the modifying effects on the induction of SCEs and chromosome aberrations by mutagens were complicated. MMC- and UV-induced SCEs and chromosome aberrations were suppressed by the posttreatment with tea tannin components at low concentrations (less than or equal to 6.7 micrograms/ml) with S9 mix. At a high concentration of tea tannin components (20 micrograms/ml) with S9 mix, a co-mutagenic effect was observed. The modifying effects of tea tannin components were shown to occur in the G1 phase of the cell cycle. In cells from a patient with xeroderma pigmentosum (XP) and a normal human embryo, MMC-induced SCEs were suppressed by the posttreatment with tea tannin components in the presence of S9 mix, and enhanced in the absence of S9 mix. On the other hand, tea tannin components modified SCE frequencies in UV-irradiated normal human cells but not in UV-irradiated XP cells. Our results suggested that tea tannin components themselves inhibited DNA-excision repair and resulted in a co-mutagenic effect, while in the presence of S9 mix metabolites of tea tannin components promoted DNA-excision repair activity and resulted in an antimutagenic effect. MMC-induced chromosome aberrations in mouse bone marrow cells were suppressed by the pretreatment with green tea and black tea tannin mixture.

Animals↗
PubMed1996

Atrial natriuretic factor modifies the composition of induced-salivary secretion in the rat.

We have previously reported that although the atrial natriuretic factor (ANF) was not a sialogogic agonist, it enhanced cholinergic, alpha-adrenergic and peptidergic (substance P) stimulated salivation in the submaxillary and parotid gland of the rat. The purpose of the present work was to study whether ANF modified the composition of agonist-induced saliva in the rat. Results showed that in the submaxillary gland, ANF increased sodium and decreased potassium excretion when salivation was stimulated by methacholine (MC) or substance P (SP). However, when salivation was induced by methoxamine (MX), ANF only increased sodium excretion. On the other hand, in the parotid gland, ANF increased both sodium and potassium excretion when salivation was induced either by MC or SP but did not modify electrolyte output in MX induced salivary secretion. Protein output and amylase activity were not modified by the presence of ANF when the aforementioned sialogogic agonists were used to elicit salivation in either gland. Although ANF did not modify the volume of isoproterenol (IP) induced saliva, it increased protein output in both glands and it increased amylase activity in the parotid gland. The present results suggest that ANF may play a role in the modulation of salivary secretion in the parotid and submaxillary glands of the rat. ANF effect is likely to be mediated by modifications in the calcium level linked to phosphoinositide metabolism within the acinar and/or the ductal cells of the salivary glands.

Animals↗
PubMed1989

Creatine kinase is modified by 2-chloromercuri-4-nitrophenol at the active site thiols with complete inactivation.

Creatine kinase modified by mercurials has been reported to be fully reactive as the native enzyme. This was ascribed to the modification of a second class of thiol groups instead of the reactive thiols at the active site (Laue, M.C. and Quiocho, F.A. (1977) Biochemistry 16, 3838-3845). It has now been shown by spectrophotometric titration and fluorescence studies that 2-chloromercuri-4-nitrophenol (MNP) reacts preferentially with the active-site thiol. Moreover, if the activity of the modified enzyme is determined in the absence of added bovine serum albumin or other enzymes, as usually employed in coupled activity assay systems for creatine kinase, the modified enzyme is completely inactive. Addition of an excess of bovine serum albumin or rabbit muscle glyceraldehyde-3-phosphate dehydrogenase restores the activity of the enzyme to over 80% of its original level. It appears that the active thiol groups at the active site of creatine kinase are after all modified by MNP with complete inactivation.

Animals↗
PubMed1995

Beta-thiopropionyl cytochromes c modified at lysyl residues: preparation and characterization of the monosubstituted horse cytochromes c.

beta-Thiopropionyl derivatives of horse cytochrome c singly modified at each of 18 different lysine epsilon-amino groups have been prepared using sulfosuccinimidyl-2-(biotinamido)ethyl-1,3-dithiopropionate and purified to homogeneity by high-pressure liquid chromatography. These derivatives were characterized by determination of: (i) the location of the modification; (ii) reduction potentials; (iii) visible and NMR spectra: and by (iv) measurement of electron transfer activity with cytochrome-c oxidase. No significant changes in structure were indicated, except for the ferric forms of the derivatives modified at lysines 72, 73, and 79 which are discussed separately. The electron transfer activity of the beta-thiopropionyl cytochromes c with bovine heart cytochrome-c oxidase was decreased to extents dependent on the position of the modification. Aminoethylation, a secondary modification which reverses the charge change, restored the electron transfer rate to that observed with the unmodified cytochrome c, irrespective of the location of the primary modification. These results afford a direct experimental demonstration that alterations in kinetics with physiological electron transfer partners resulting from modifications which cause a change of the charge of surface side chains are solely due to the electrostatic effects. Of the many chemically modified cytochromes c prepared to date, the singly substituted beta-thiopropionyl cytochromes c are likely to be particularly useful as the thiol allows covalent linkage of any sulfhydryl-reactive reagent to a well-defined location on the protein surface by a simple procedure, even when the secondary modifier is relatively unstable, a crucial advantage not otherwise readily achieved.

Amino Acid Sequence↗
PubMed1991

Comparison between semisolid Rappaport and modified semisolid Rappaport-Vassiliadis media for the isolation of Salmonella spp. from foods and feeds.

Two semisolid media poured in petri dishes, semisolid Rappaport and modified semisolid Rappaport Vassiliadis were compared for the recovery of Salmonella spp. from 154 high- and low-moisture foods and feeds. Semisolid media were inoculated after pre-enrichment in buffered peptone water and after enrichment in Müller-Kauffmann tetrathionate broth and selenite cystine broth. Also a conventional procedure was used, where the enrichment broths were streaked on Brilliant Green and bismuth sulphite agars. Of 62 samples found positive for Salmonella by one or more methods, semisolid Rappaport detected all of them and 60 when inoculated directly from the pre-enrichment broth. Modified semisolid Rappaport-Vassiliadis gave only 20 positive samples. The difference in productivity between semisolid Rappaport and the other media poured in plates (modified semisolid Rappaport-Vassiliadis, Brilliant Green and bismuth sulphite agar) was statistically significant (P less than 0.001). The incubation temperature recommended for modified semisolid Rappaport-Vassiliadis (42 degrees C) was found to be too high. By comparison to the other media, semisolid Rappaport gave a 500% increase in the detection of the enteritidis serotype of Salmonella.

Animal Feed↗
PubMed1990

Repair of acetyl-aminofluorene modified pBR322 DNA in Xenopus laevis oocytes and eggs; effect of diadenosine tetraphosphate.

Using Xenopus laevis oocytes and unfertilized eggs, we have developed a system which allows the study of DNA repair upon microinjection of pBR 322 DNA which has been previously modified in vitro by N-acetyl-aminofluorene, under controlled conditions. In unfertilized eggs, an efficient repair of pBR-18AAF DNA takes place, leading to a restoration of the transforming activity of the plasmid DNA towards Escherichia coli. The repaired DNA is even efficiently replicated, the egg being "activated" by the microinjection. In the oocyte, a partial repair is observed as shown by the incorporation of labelled dCTP in the modified plasmid DNA, even in the presence of aphidicolin, an inhibitor of DNA polymerase alpha. However, the repair appears to be very limited, since it does not restore the transforming activity of the modified plasmid DNA. This inefficient repair in the oocyte may be due to the rapid packaging of foreign DNA into a minichromosome and/or to a very low level of DNA polymerase beta. This system was used to study the effect of diadenosine tetraphosphate (Ap4A) on DNA repair. Ap4A seems not to interfere with repair processes in the oocyte, but significantly inhibits the replication following the repair of AAF-modified plasmid DNA in unfertilized eggs. These results suggest that Ap4A could be involved in switching off the replication machinery when DNA is badly damaged, thus helping to avoid the perpetuation of DNA modifications in the daughter cells. This hypothesis is consistent with many previous reports on the accumulation of dinucleoside polyphosphates under stress conditions, which are known to result in modification of DNA.

2-Acetylaminofluorene↗
PubMed1995

Implications of a functional large ribosomal RNA with only three modified nucleotides.

The sequence and structure of the peptidyl transferase region of large subunit ribosomal RNA is highly conserved and specific modified nucleotides could be important structural or functional elements in the catalytic center responsible for peptide bond formation. In fact, it has not been possible to reconstitute active E coli 50S subunits from in vitro transcripts of 23S rRNA and total 50S proteins. It is significant therefore, that the PET56 gene of yeast encodes an essential ribose methyltransferase that specifically modifies a universally conserved nucleotide, G2270, in the peptidyl transferase center of the mitochondrial large ribosomal RNA (21S). Since the loss of this modification in yeast mitochondrial 21S rRNA severely affects the assembly of 54S subunits, it is likely that the analogous 2'-O-methylguanosine at position 2251 (Gm2251) in E coli 23S rRNA is also required for the assembly of 50S subunits. Gm could be a critical structural determinant for the correct folding of the rRNA, the binding of one or more ribosomal proteins, or the interaction of the rRNA with tRNA. Previous work has shown that the mitochondrial large rRNAs are minimally modified relative to the E coli and eukaryotic cytoplasmic rRNAs. By direct chemical analysis using combined high performance liquid chromatography-mass spectrometry, the modification status of the yeast mitochondrial rRNAs was reexamined, revealing the presence of Gm, Um and pseudouridine (psi) in 21S rRNA. The Um was mapped to nucleotide 2791, which corresponds to the ribose methylated and universally conserved U2552 in E coli 23S rRNA, and the psi has been recently mapped to position 2819, which corresponds to psi 2580 in E coli 23S rRNA. The retention of Um and psi nucleotides in the peptidyl transferase center of the otherwise minimally modified mitochondrial rRNAs suggests that these modifications, like Gm2270, might be essential for ribosome assembly or function or both.

Base Sequence↗