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Biomedical subjects

F Johnson

Publications and source records attributed to F Johnson.

At least 37 records · Page 2Linked to original sources
PubMed1989

NMR studies of abasic sites in DNA duplexes: deoxyadenosine stacks into the helix opposite acyclic lesions.

Proton and phosphorus NMR studies are reported for two complementary nonanucleotide duplexes containing acyclic abasic sites. The first duplex, d(C-A-T-G-A-G-T-A-C).d(G-T-A-C-P-C-A-T-G), contains an acyclic propanyl moiety, P, located opposite a deoxyadenosine at the center of the helix (designated APP 9-mer duplex). The second duplex, d(C-A-T-G-A-G-T-A-C).d(G-T-A-C-E-C-A-T-G), contains a similarly located acyclic ethanyl moiety, E (designated APE 9-mer duplex). The ethanyl moiety is one carbon shorter than the natural carbon-phosphodiester backbone of a single nucleotide unit of DNA. The majority of the exchangeable and nonexchangeable base and sugar protons in both the APP 9-mer and APE 9-mer duplexes, including those at the abasic site, have been assigned by recording and analyzing two-dimensional phase-sensitive NOESY data sets in H2O and D2O solution between -5 and 5 degrees C. These spectroscopic observations establish that A5 inserts into the helix opposite the abasic site (P14 and E14) and stacks between the flanking G4.C15 and G6.C13 Watson-Crick base pairs in both the APP 9-mer and APE 9-mer duplexes. The helix is right-handed at and adjacent to the abasic site, and all glycosidic torsion angles are anti in both 9-mer duplexes. Proton NMR parameters for the APP 9-mer and APE 9-mer duplexes are similar to those reported previously for the APF 9-mer duplex (F = furan) in which a cyclic analogue of deoxyribose was embedded in an otherwise identical DNA sequence [Kalnik, M. W., Chang, C. N., Grollman, A. P., & Patel, D. J. (1988) Biochemistry 27, 924-931]. These proton NMR experiments demonstrate that the structures at abasic sites are very similar whether the five-membered ring is open or closed or whether the phosphodiester backbone is shortened by one carbon atom. Phosphorus spectra of the APP 9-mer and APE 9-mer duplexes (5 degrees C) indicate that the backbone conformation is similarly perturbed at three phosphodiester backbone torsion angles. These same torsion angles are also distorted in the APF 9-mer but assume a different conformation than those in the APP 9-mer and APE 9-mer duplexes.

Base Composition↗
PubMed1989

Aggression in male mice: rapid-onset attack of lactating female mice following termination of hyperphysiological testosterone treatment.

Gonadally-intact or castrated and testosterone-(T) treated male mice display aggressive behavior towards olfactory-bulbectomized male (OBM) stimuli, but not towards lactating female (LF) stimuli. By comparison, T-treated female mice display aggressive behavior towards both OBM and LF stimuli. The purpose of the present experiment was to determine if male mice given hyperphysiological T-treatment would display "female-typical" attack of OBM and LF stimuli. Hyperphysiological T-stimulation did not lead to the display of aggressive behavior towards OBM and LF stimuli; only OBM stimuli were attacked, suggesting a qualitative behavioral sex difference in response to T. However, the major finding of this study occurred following the termination of T-treatment. Castrated males that had previously received hyperphysiological T-treatment began to attack LF stimuli within 48 hr of treatment termination. By comparison, castrated males that had previously received physiological T-stimulation, as well as a gonadally-intact control group, generally began to attack LF stimuli 3-4 weeks following treatment-termination/castration. It is suggested that this unusual treatment-termination-induced behavioral display occurs via neurochemical mediation.

Aggression↗
PubMed1989

Differential effects of dietary fat on the tissue-specific expression of the apolipoprotein A-I gene: relationship to plasma concentration of high density lipoproteins.

Isocaloric substitution of polyunsaturated fat for saturated fat reduces concentrations of total plasma cholesterol and high density lipoproteins (HDL) in nonhuman primates. The biochemical mechanisms through which polyunsaturated fat lowers plasma HDL concentrations are not well understood but must involve changes in HDL production or HDL clearance from plasma, or both. To determine whether dietary polyunsaturated fat (P/S = 2.2) alters apolipoprotein (apo) A-I production, African green monkeys (Cercopithecus aethiops) were fed diets containing polyunsaturated fat or saturated fat (P/S = 0.3) each in combination with high (0.8 mg/kcal) and low (0.03 mg/kcal) amounts of dietary cholesterol. Animals fed polyunsaturated fat at either cholesterol level had lower plasma concentrations of total cholesterol and HDL cholesterol. Plasma apoA-I concentration was reduced by 16% by polyunsaturated fat in the high cholesterol group. The rate of hepatic apoA-I secretion, as estimated by the accumulation of perfusate apoA-I during recirculating liver perfusion, was reduced by 19% in animals consuming the high cholesterol, polyunsaturated fat diet. Hepatic apoA-I mRNA concentrations, as measured by DNA-excess solution hybridization, also were reduced by 22% in the high cholesterol, polyunsaturated fat-fed animals. In contrast, intestinal apoA-I mRNA concentrations were not altered by the type of dietary fat. Plasma apoA-II and hepatic apoA-II mRNA concentrations also were not altered by the type of dietary fat. These data indicate that dietary polyunsaturated fat can selectively alter the expression of the apoA-I gene in a tissue-specific manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Apolipoprotein (apo) A-I production and mRNA abundance explain plasma apoA-I and high density lipoprotein differences between two nonhuman primate species with high and low susceptibilities to diet-induced hypercholesterolemia.

Earlier studies have shown that African green monkeys develop a more modest hypercholesterolemia, higher high density lipoprotein (HDL) concentrations, and less atherosclerosis than cynomolgus monkeys fed diets with the same cholesterol content. In the present study, cynomolgus monkeys were fed less cholesterol than was fed to African green monkeys to induce equivalent hypercholesterolemia in both species. African green monkeys still had 2-fold higher plasma HDL cholesterol concentrations and 2.7-fold higher plasma apolipoprotein (apo) A-I concentrations. Therefore, the higher HDL concentration in African green monkeys appears to result from factors that act independently of dietary cholesterol intake or total plasma cholesterol concentration. Two aspects of HDL production were examined to determine the metabolic basis of the species difference in HDL concentration. The rate of hepatic apoA-I secretion, as estimated by the accumulation of apoA-I in the medium during recirculating liver perfusion, was 5-fold higher in livers of African green monkeys. In addition, the concentration of apoA-I mRNA was 2-fold higher in the liver and 3.7-fold higher in the intestine of African green monkeys. Taken together, these findings indicate that differences in apoA-I production in the liver and small intestine are large enough to be responsible for the differences in the plasma concentrations of HDL and apoA-I between these species. Factors which regulate apoA-I secretion, including modulation of tissue apoA-I mRNA concentrations, are important determinants of plasma HDL concentrations and may contribute to the relative resistance of African green monkeys to dietary cholesterol-induced hypercholesterolemia and atherosclerosis. ApoA-I mRNA was also detected at low levels in the kidney and testis of African green and cynomolgus monkeys but not in the adrenal or brain. The tissue distribution and abundance of apoA-I mRNA in peripheral tissues was very different than that seen for apoE mRNA. Kidney and testis apoA-I mRNAs were the same size as liver apoA-I mRNA when examined by Northern blot analysis. Testis apoA-I mRNA appeared to be functionally active as judged by its presence in cytoplasmic polyribosomes. The low levels of apoA-I expression in kidney and testis are unlikely to contribute significantly to the plasma apoA-I pool but might function in some aspect of local lipid metabolism within these tissues.

Animals↗
PubMed1988

Aggression in adult female mice: chronic testosterone treatment induces attack against olfactory bulbectomized male and lactating female mice.

Ovariectomized adult female CFW mice were given a series of tests for fighting behavior against olfactory bulbectomized male and lactating female mice prior to (for 2 weeks), and during (for 4 weeks) chronic treatment with testosterone propionate. While ovariectomized, 40% attacked the lactating female and 13.3% attacked the olfactory bulbectomized male. While ovariectomized and testosterone-treated, 73.3% attacked the lactating female and 60% attacked the olfactory bulbectomized male. However, during the initial 2 weeks of testosterone treatment there was an inhibition of attack against the lactating female. This was followed by a facilitation of attack against the olfactory bulbectomized male and the lactating female during the third and fourth weeks of testosterone treatment. When compared with a previous experiment showing that male mice, gonadally-intact or castrated and testosterone-treated, discriminate between these two stimuli (only the bulbectomized male is attacked), the present data do not support the notion that sexual differentiation of mouse aggression is due solely to the development of a limited sensitivity to testosterone in females.

Aggression↗
PubMed1988

Testicular hormones reduce individual differences in the aggressive behavior of male mice: a theory of hormone action.

A chronology of theoretical development in studies of the role of testicular hormones in murine aggression is presented. Evidence which brings into question the generality of current theory is reviewed, and the implications of this evidence for the direction of future research are discussed. A new method by which to characterize individual differences in aggressive behavior is described, and recent data which provide the basis for the development of a new theory are presented. It is theorized that testicular hormones reduce individual differences in the aggressive behavior of male mice, and that this behavioral "homogenization" is mediated by a testicular-hormone regulated "discrimination mechanism," possibly localized within the mouse olfactory system. The generality of this theory and the implications for other hormone/behavior systems are also discussed.

Aggression↗
PubMed1988

Targeted mutations induced by a single acetylaminofluorene DNA adduct in mammalian cells and bacteria.

Mutagenic specificity of 2-acetylaminofluorene (AAF) has been established in mammalian cells and several strains of bacteria by using a shuttle plasmid vector containing a single N-(deoxyguanosin-8-yl)acetylaminofluorene (C8-dG-AAF) adduct. The nucleotide sequence of the gene conferring tetracycline resistance was modified by conservative codon replacement so as to accommodate the sequence d(CCTTCGCTAC) flanked by two restriction sites, Bsm I and Xho I. The corresponding synthetic oligodeoxynucleotide underwent reaction with 2-(N-acetoxy-N-acetylamino)-fluorene (AAAF), forming a single dG-AAF adduct. This modified oligodeoxynucleotide was hybridized to its complementary strand and ligated between the Bsm I and Xho I sites of the vector. Plasmids containing the C8-dG-AAF adduct were used to transfect simian virus 40-transformed simian kidney (COS-1) cells and to transform several AB strains of Escherichia coli. Colonies containing mutant plasmids were detected by hybridization to 32P-labeled oligodeoxynucleotides. Presence of the single DNA adduct increased the mutation frequency by 8-fold in both COS cells and E. coli. Over 80% of mutations detected in both systems were targeted and represented G.C----C.G or G.C----T.A transversions or single nucleotide deletions. We conclude that modification of a deoxyguanosine residue with AAF preferentially induces mutations targeted at this site when a plasmid containing a single C8-dG-AAF adduct is introduced into mammalian cells or bacteria.

2-Acetylaminofluorene↗
PubMed1988

DST results in nonpsychotic depressed outpatients.

In two studies using the dexamethasone suppression test (DST) to evaluate the efficacy of newer antidepressants in depressed outpatients, the authors found a DST nonsuppression rate of 13% (11 of 86 patients). Thirty-three of the DST suppressors received an antidepressant and 42 received placebo; the drug-treated group showed a significant therapeutic response. The low rate of DST nonsuppression in these depressed outpatients, a finding consistent with that of other investigators, does not confirm or refute reports that these patients are relatively resistant to placebo in comparison with active medication. The authors recommend that DST results not be used as selection criteria in studies assessing newer therapies for depressed outpatients.

Adult↗
PubMed1988

Teenage pregnancy: issues, interventions, and direction.

The positive health trends and overall improvement in health status among the US population cause health professionals, human service providers, educators, and policy makers to be encouraged about the fitness of our nation. When taking a closer look at these trends and related changes, however, a dilemma exists among a portion of our population that cannot be dismissed. While the health status of the US population as a whole has steadily improved over the past decades, such progress has not been sustained for adolescents. In fact, adolescence (15 to 21 years of age) is the only age group in which mortality rates have increased over the past decade.One of the principal threats to adolescent health is unwanted pregnancy. More than one million teenage pregnancies occur each year in the United States, 75 percent of which are unintended. Teenage pregnancy is a multifaceted problem that requires multifaceted intervention. It is not just the pregnant teenager's problem either, but may involve up to three generations of family members and a host of other significant relationships. The impact and cost to society can become staggering.If such a great proportion of these pregnancies are unintended, what steps can be taken to offer acceptable and accessible alternatives to adolescents? An assessment of the magnitude of this problem, its impact on the family and society, and the measures implemented to date reveal a major challenge facing our policy makers, health and human service providers, and concerned citizenry.

Adolescent↗
PubMed1988

Microdistribution and local dosimetry of 226Ra in trabecular bone of the beagle.

Sections of lumbar vertebral bodies of young adult beagle dogs have been analyzed autoradiographically to characterize and quantify the local distribution of 226Ra by means of a scanning microscope photometer. The animals received a single injection of 355 kBq/kg body weight and were serially sacrificed at 5 to 1381 days postinjection. Hotspot concentrations decreased from about 51 kBq/g bone at 5 days to 20 kBq/g at 1381 days postinjection. The diffuse concentration changed from 8.3 to 1.9 kBq/g. The mean 226Ra concentration in the trabecular areas scanned was initially higher and at the end of the observation period lower than the average calculated for the whole lumbar vertebral column. Density and area of, and fraction of bone activity in, hotspots virtually remained constant. With time hotspots tended to become translocated into bone volume. Mean dose rates to lining cells from both hotspots and diffuse labels decreased from about 210 mGy/d at early postinjection times to 105 mGy/d. This corresponds to 2.5 to 1.1 times the average skeletal dose rate. A discussion of the level of irradiation in terms of hit frequencies shows that osteoblasts in the initial phase of hotspot formation receive about 60 hits to their nucleus for the duration of bone formation. After about 6 months, however, the 226Ra concentration in new bone and the corresponding hit frequency appears to be low enough that interference with bone formation is unlikely. Morphometric measurements showed that abnormal bone accretion and thickening of trabeculae occurred. This was interpreted as an imbalance between bone formation and resorption. Both formation and resorption seem to be substantially lowered compared to control animals.

Animals↗
PubMed1987

Oligodeoxynucleotides containing synthetic abasic sites. Model substrates for DNA polymerases and apurinic/apyrimidinic endonucleases.

A synthetic procedure has been developed by which stable abasic sites are introduced into oligodeoxynucleotides at any desired position in the sequence. A modified tetrahydrofuran moiety, isosteric with 2'-deoxyribofuranose, serves as a structural analog of the natural apurinic/apyrimidinic site. We have also prepared oligodeoxynucleotides that lack cyclic structure at the abasic site but retain the carbon atoms of the phosphodiester backbone. These synthetic oligodeoxynucleotides are cleaved on the 5' side of the abasic site by endonuclease IV and by exonuclease III; they serve also as templates for avian myeloblastosis virus reverse transcriptase, Escherichia coli DNA polymerase I (Klenow fragment), and calf thymus DNA polymerase-alpha. Extension of primed templates by these DNA polymerases is blocked initially at the position immediately 3' to the abasic site; nucleoside monophosphates are subsequently incorporated opposite the lesion. The nucleotide most frequently incorporated opposite all abasic sites, regardless of structure, is dAMP. Significant "readthrough" at the abasic site was observed in experiments using avian myeloblastosis virus reverse transcriptase and DNA polymerase-alpha and, to a much lesser degree, with DNA polymerase I. We conclude that a modified tetrahydrofuran group can serve as a stable structural analog of 2'-deoxyribose in the apurinic/apyrimidinic site. These modified oligodeoxynucleotides should prove useful for studies of chemical mutagenesis.

Animals↗
PubMed1987

Individual differences in the attack behavior of male mice: a function of attack stimulus and hormonal state.

Male CFW mice were tested for fighting behavior directed against olfactory bulbectomized male mice and against lactating female mice. Some males were tested with each stimulus type before and after castration. Some males were tested first following castration and then after testosterone treatment. All gonadally intact males attacked bulbectomized males and 25% attacked lactating females. After castration 81% attacked males on at least one occasion and 62% began to attack lactating females, although individual differences in the pattern of post-castration behavior were large. Individual differences in attack behavior were also large in males whose first tests followed castration. Of these, 60% attacked both stimuli. Following testosterone treatment, attack against males increased while attack against females was inhibited. Hormonal stimulation reduced individual differences in behavior and increased males' discrimination between the two types of stimuli.

Aggression↗
PubMed1987

Vacuum extraction versus forceps delivery: indications and complications, 1979 to 1984.

Two hundred fifty-six vacuum extractions and 300 randomly chosen forceps deliveries were analyzed retrospectively. Vacuum extraction use increased from 0.3 to 3.1%, while forceps use declined from 10.1 to 4.9% over a five-year period. No differences were found in indications for vacuum extraction and forceps, but the preapplication position differed (occiput posterior or transverse in 81.2% in the vacuum group and 27% in forceps patients). Preapplication station also differed, with 59.8% of vacuum extraction at +1 or higher stations, compared with 9% of forceps. Under these conditions we found less maternal trauma, similar failure rates (3.9 versus 2%), and no difference in maternal morbidity. There was a higher incidence of shoulder dystocia and neonatal jaundice in the vacuum group, but cephalohematoma frequency did not differ significantly (3.9% vacuum extraction, 4.3% forceps). Cosmetic injuries (ecchymoses, abrasions) were more likely with vacuum extraction than with forceps (44.1 versus 29.5%). One death occurred in each group. Vacuum extraction replaced midforceps in our institution in the study period. We consider vacuum extraction a useful technique to teach house staff in view of today's decreasing instrumental delivery rate.

Birth Injuries↗
PubMed1986

Streptonigrin. 1. Structure-activity relationships among simple bicyclic analogues. Rate dependence of DNA degradation on quinone reduction potential.

A series of simple aza and diaza bicyclic quinones related to the AB ring system of streptonigrin (1) have been synthesized and tested in vitro for their ability to degrade DNA under conditions similar to those used with the parent drug. The results obtained from a study of 22 quinones indicate that there is a quantitative linear relationship between their reduction potentials and the rate at which they degrade DNA under identical conditions in vitro. Almost all of the synthetic substances were superior to 1 in their DNA-degrading ability.

DNA↗