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Biomedical subjects

N Brown

Publications and source records attributed to N Brown.

At least 163 records · Page 9Linked to original sources
PubMed1991

Interaction of GTP derivatives with cellular and oncogenic ras-p21 proteins.

A series of N2-substituted guanosine 5'-triphosphates was synthesized from the corresponding nucleosides. The nucleosides were prepared by treatment of N2-substituted guanines with tetra-O-acetylribose under conditions which maximized the yield of the 9-beta-guanosine isomers. These nucleotides and several sugar- and base-modified analogues of GTP were tested for their ability to bind to cellular and oncogenic forms of the GTP/GDP binding proteins, Ha-ras-p21. Several N2-substituted GTPs showed affinities higher than that of GDP itself, and the N2-[p-(n-butyl)phenyl] derivative bound to the oncogenic mutant, Leu-61 p21, twice as strongly as to the cellular protein. Changes in relative affinities of the nucleotides are discussed with reference to reported crystallographic structures of p21.

Genes, ras↗
PubMed1991

A mathematical model for the formation of cerebral aneurysms.

Cerebral aneurysms are hypothesized to be acquired lesions resulting from a loss of static equilibrium in the apical region of the bifurcation, which causes the opening angle of the bifurcation to change during the cardiac cycle. Repeated dynamic cycling may disrupt wall elements in a manner analogous to a wire breaking with repeated bending and result in the formation of an aneurysm. A mathematical model that predicts the geometry of arterial bifurcations is proposed. The model predicts that the transmural pressure in the larger branch is greater than or equal to that in the smaller branch and that the larger branch makes a smaller angle with the direction of the parent artery [corrected]. Bifurcations with smaller area ratios (the sum of the luminal areas of the branches divided by the luminal area of the parent artery) have smaller opening angles. When the area ratio is 1.0, the opening angle is about 90 degrees. The model concludes that the opening angle is constant during the cardiac cycle if the fractional change in the radii of the daughter and parent arteries is the same for any increase in blood pressure and if the ratio of transmural pressures in the parent and daughter branches does not change during the cardiac cycle. Otherwise, the bifurcation is considered predisposed to the development of an aneurysm.

Biomechanical Phenomena↗
PubMed1991

Diplomatosis.

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Education, Medical, Graduate↗
PubMed1990

Molecular cloning, regulation, and complete sequence of a hemocyanin-related, juvenile hormone-suppressible protein from insect hemolymph.

A cDNA library was prepared from mRNA isolated from the lepidopteran Trichoplusia ni during larval-pupal metamorphosis. Differential probing was used to identify clones for mRNAs which are suppressible by exogenous juvenile hormone treatment. In vitro transcribed cRNAs from these clones were translated in vitro and challenged with antiserum specific for a known acidic, juvenile hormone-suppressible hemolymph protein (AJSP-1) that is associated with larval metamorphosis. Three clones were found which encoded immunoreactive translation products; their identity was confirmed by comparison of the N-terminal sequence of the mature AJSP-1 protein with the cDNA sequence. As inferred from the cDNA sequence, the protein encompasses 704 amino acid residues, including a N-terminal signal peptide; widely distributed as well as more localized stronger sequence similarities indicate that the protein is distantly related to hemocyanins and hemocyanin-like insect proteins. However, on the basis of amino acid sequence and composition, immunological reactivity, and hormonal sensitivity, the protein is distinct from previously described insect proteins. Its juvenile hormone suppressibility can be ascribed to suppression of the mRNA. RNA blot analysis using the cloned cDNA as a probe demonstrated that the transcript (approximately 2.8 kilobases) is of very low abundance during the penultimate stadium but becomes very abundant during the last larval stadium, when juvenile hormone rapidly declines. Furthermore, treatment of larvae with a juvenile hormone analog strongly suppresses the abundance of the message.

Amino Acid Sequence↗
PubMed1990

Supplemental putrescine reverses ethanol-associated inhibition of liver regeneration.

Biosynthesis of the polyamines, putrescine, spermidine and spermine, is required for DNA synthesis and liver regeneration after partial hepatectomy. Chronic ethanol consumption impairs polyamine synthesis during the prereplicative phase after partial hepatectomy. To determine whether this delay in polyamine synthesis contributes to ethanol's inhibition of liver regeneration, the ability of supplemental putrescine to improve regeneration in ethanol-fed rats was tested. Chronically ethanol-fed rats and isocalorically maintained controls underwent partial hepatectomy and were injected intraperitoneally with saline or putrescine (0.03 or 0.30 mmol/kg) at 0, 4, 8 and 12 hr after partial hepatectomy. Rats were killed at 24, 48 or 72 hr, 1 hr after exposure to [3H]thymidine, so that DNA synthesis could be estimated. DNA synthesis was significantly inhibited in ethanol-fed rats treated with saline compared with saline-treated pair-fed controls. Supplemental putrescine did not affect DNA synthesis in pair-fed rats. In contrast, putrescine significantly improved [3H]thymidine incorporation 24 to 72 hr after partial hepatectomy in ethanol-fed rats. Intraperitoneal injection of putrescine (1.2 mmol/kg) at the time of partial hepatectomy increased hepatic polyamine concentrations for the first 6 hr after partial hepatectomy despite significantly inhibiting the activity of ornithine decarboxylase, the rate-limiting enzyme for polyamine synthesis, in both groups. Hepatic polyamine levels after putrescine injection were greater in ethanol-fed rats than in similarly treated controls. These data suggest that putrescine treatment triggers events that normalize DNA synthesis in ethanol-fed rats. These results confirm the hypothesis that ethanol's antiregenerative mechanism intimately involves inhibition of putrescine synthesis.

Animals↗
PubMed1990

Isolation of omnipotent suppressors in an [eta+] yeast strain.

Omnipotent suppressors decrease translational fidelity and cause misreading of nonsense codons. In the presence of the non-Mendelian factor [eta+], some alleles of previously isolated omnipotent suppressors are lethal. Thus the current search was conducted in an [eta+] strain in an effort to identify new suppressor loci. A new omnipotent suppressor, SUP39, and alleles of sup35, sup45, SUP44 and SUP46 were identified. Efficiencies of the dominant suppressors were dramatically reduced in strains that were cured of non-Mendelian factors by growth on guanidine hydrochloride. Wild-type alleles of SUP44 and SUP46 were cloned and these clones were used to facilitate the genetic analyses. SUP44 was shown to be on chromosome VII linked to cyh2, and SUP46 was clearly identified as distinct from the linked sup45.

Alleles↗
PubMed1990

Sequence and functional similarity between a yeast ribosomal protein and the Escherichia coli S5 ram protein.

The accurate and efficient translation of proteins is of fundamental importance to both bacteria and higher organisms. Most of our knowledge about the control of translational fidelity comes from studies of Escherichia coli. In particular, ram (ribosomal ambiguity) mutations in structural genes of E. coli ribosomal proteins S4 and S5 have been shown to increase translational error frequencies. We describe the first sequence of a ribosomal protein gene that affects translational ambiguity in a eucaryote. We show that the yeast omnipotent suppressor SUP44 encodes the yeast ribosomal protein S4. The gene exists as a single copy without an intron. The SUP44 protein is 26% identical (54% similar) to the well-characterized E. coli S5 ram protein. SUP44 is also 59% identical (78% similar) to mouse protein LLrep3, whose function was previously unknown (D.L. Heller, K.M. Gianda, and L. Leinwand, Mol. Cell. Biol. 8:2797-2803, 1988). The SUP44 suppressor mutation occurs near a region of the protein that corresponds to the known positions of alterations in E. coli S5 ram mutations. This is the first ribosomal protein whose function and sequence have been shown to be conserved between procaryotes and eucaryotes.

Amino Acid Sequence↗
PubMed1990

Mutations in RAD6, a yeast gene encoding a ubiquitin-conjugating enzyme, stimulate retrotransposition.

The Saccharomyces cerevisiae DNA repair gene RAD6 encodes a ubiquitin-conjugating enzyme which polyubiquitinates histones in vitro. Here we show that mutations in rad6 increase the frequency of transposition of the retrotransposon Ty into the CAN1 and URA3 loci. Using isogenic RAD6 and rad6 strains, we measured a more than 100-fold increase in the spontaneous rate of retrotransposition due to rad6, although there was no increase in the Ty message level. This is the first time that a mutation in a host gene has been shown to result in an increased rate of retrotransposition.

Blotting, Northern↗
PubMed1989

Up-promoter mutations in the positively-regulated mer promoter of Tn501.

Transcription from the mer promoter of transposon Tn501 is repressed by MerR (the product of the merR gene) in the absence of Hg2+, and activated by MerR in the presence of Hg2+. In the absence of MerR, the mer promoter has weak constitutive activity. The DNA sequence of the mer promoter shows candidate -35 and -10 sequences at the unusually high spacing of 19 base-pairs. We have selected for spontaneous mutations in the mer promoter that confer an up-promoter phenotype. Four different mutants have been isolated. Three of these are single base-pair deletions between the -10 and -35 sequences. A fourth removes the -10 sequence entirely, and places a second potential -10 sequence 17 base-pairs from the -35 sequence. None of these mutant promoters are induced by MerR in the presence of Hg2+. Two of them are repressed by MerR irrespective of the presence or absence of Hg2+. Models for the mode of action of the MerR protein are discussed in the light of these results. Our data support a mechanism in which the MerR protein in the presence of Hg2+ acts to change the conformation of DNA in the mer promoter.

Bacterial Proteins↗
PubMed1989

ATL-derived factor (ADF), an IL-2 receptor/Tac inducer homologous to thioredoxin; possible involvement of dithiol-reduction in the IL-2 receptor induction.

HTLV-I transformed T cells not only express a large number of interleukin-2 receptors [IL-2R/p55(Tac)], but also produce a factor named ATL-derived factor (ADF) that augments the expression of IL-2R/p55(Tac). Based on a partial N-terminal amino acid sequence, complementary DNA (cDNA) clones for human and mouse ADF were isolated and sequenced. Recombinant ADF produced by COS-7 monkey kidney cells showed IL-2R/Tac inducing activity on YT cells, which are sensitive for ADF. ADF mRNA was strongly expressed in HTLV-I(+) T cells lines, but not in inactivated cells (THP-1, unstimulated PBMC). Furthermore, in normal human peripheral blood mononuclear cells, the expression of ADF mRNA was enhanced by mitogens or phorbol myristate acetate, suggesting a possible involvement of ADF in the lymphocyte activation. Homology analysis revealed an unexpected relationship between ADF and dithiol-reducing enzyme, thioredoxin, involved in many important biological reactions such as the conversion of ribonucleotides into deoxyribonucleotides, or the stabilization of glucocorticoid receptors. The biological significance of the generation of a redox potential in lymphocyte activation, and the possible involvement of dithiol reduction in the induction of IL-2R/Tac are discussed.

Amino Acid Sequence↗
PubMed1989

Analysis of yeast retrotransposon Ty insertions at the CAN1 locus.

The target site distribution for 55 independent Ty insertions that inactivate the function of the Saccharomyces cerevisiae CAN1 gene is reported. Under some selection conditions Ty elements inserted preferentially into the promoter and exhibited an orientation bias. In contrast, under other conditions no insertions were detected in the promoter region and transposition appeared to occur randomly throughout the CAN1 coding sequence. These results show that the target site distribution for Ty insertions may be a function of the selection conditions.

Base Sequence↗
PubMed1989

Fluoxetine overdose in an adolescent.

The response to and management of an acute ingestion of a large quantity of fluoxetine hydrochloride in a 13-year-old boy with Tourette's syndrome and obsessive compulsive disorder is described. The patient's symptomatic course following the ingestion included a grand mal seizure, depressed ST segments on EKG, nausea, dizziness, and headache. In general, the fluoxetine was well tolerated: all of the symptoms and signs remitted spontaneously.

Adolescent↗