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Biomedical subjects

I Molnár

Publications and source records attributed to I Molnár.

At least 37 records · Page 2Linked to original sources
PubMed1995

The adaptive advantage of phenotypic memory in changing environments.

The adaptive value of carry-over effects, the persistence of induced phenotypes for several generations despite the change in the conditions that first induced these phenotypes, is studied in the framework of a simple model. Three different organismal strategies-non-inducible (genetic), completely inducible (plastic), and intermediate (carry-over)-are compared in fitness terms within three different environments. Analytical results and numerical simulations show that carry-over effects can have an advantage in stochastic environments even over organisms with high adaptive plasticity. We argue that carry-over effects represent an adaptive mechanism on the ecological timescale that fills the gap between short-term individual adaptations and long-term evolutionary adaptations. An extension of the concept of plasticity to incorporate the time dimension and include the stability of induced phenotypes through both clonal and sexual generations, is suggested.

Adaptation, Biological↗
PubMed1995

Divergent sequence motifs correlated with the substrate specificity of (methyl)malonyl-CoA:acyl carrier protein transacylase domains in modular polyketide synthases.

The amino acid sequences of a large number of polyketide synthase domains that catalyse the transacylation of either methylmalonyl-CoA or malonyl-CoA onto acyl carrier protein (ACP) have been compared. Regions were identified in which the acyltransferase sequences diverged according to whether they were specific for malonyl-CoA or methylmalonyl-CoA. These differences are sufficiently clear to allow unambiguous assignment of newly-sequenced acyltransferase domains in modular polyketide synthases. Comparison with the recently-determined structure of the malonyltransferase from Escherichia coli fatty acid synthase showed that the divergent region thus identified lies near the acyltransferase active site, though not close enough to make direct contact with bound substrate.

Acyl Carrier Protein↗
PubMed1995

The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin.

The macrocyclic polyketides rapamycin and FK506 are potent immunosuppressants that prevent T-cell proliferation through specific binding to intracellular protein receptors (immunophilins). The cloning and specific alteration of the biosynthetic genes for these polyketides might allow the biosynthesis of clinically valuable analogues. We report here that three clustered polyketide synthase genes responsible for rapamycin biosynthesis in Streptomyces hygroscopicus together encode 14 homologous sets of enzyme activities (modules), each catalyzing a specific round of chain elongation. An adjacent gene encodes a pipecolate-incorporating enzyme, which completes the macrocycle. The total of 70 constituent active sites makes this the most complex multienzyme system identified so far. The DNA region sequenced (107.3 kbp) contains 24 additional open reading frames, some of which code for proteins governing other key steps in rapamycin biosynthesis.

Acyltransferases↗
PubMed1995

Secretory overproduction of Arthrobacter simplex 3-ketosteroid delta 1-dehydrogenase by Streptomyces lividans with a multi-copy shuttle vector.

The gene for 3-ketosteroid delta 1-dehydrogenase (ksdD) of Arthrobacter simplex was expressed in Streptomyces lividans and the secreted enzyme was overproduced by using a multi-copy shuttle vector composed of pIJ702 and pUC19. Deletional analysis of the recombinant plasmid showed that the entire coding sequence of the ksdD gene was located within a 7-kb segment of the chromosomal DNA obtained from the enzyme-producing strain of A. simplex. When S. lividans carrying the recombinant plasmid was grown in an appropriate medium, the cells produced about 100-fold more 3-ketosteroid delta 1-dehydrogenase than the original strain. Although the percentage of enzyme secreted was changed during cultivation, a maximum 55% of the enzyme was secreted into the cultured medium of S. lividans, while A. simplex did not produce the enzyme extracellularly. Secretory overproduction of 3-ketosteroid delta 1-dehydrogenase in S. lividans was also identified by sodium dodecyl sulfate/polyacrylamide gel electrophoresis and on native gel, and the enzyme reaction was confirmed by reverse-phase HPLC using 4-androstene-3,17-dione as a substrate.

Androstadienes↗
PubMed1995

IgA autoantibodies against human eye muscle antigen detected by western blotting and immunohistochemical methods in Graves' disease.

The presence of IgA autoantibodies against human eye muscle was investigated in 40 patients with Graves' disease (33 had ophthalmopathy). IgA anti-eye muscle antibodies could be demonstrated in sera of patients using western blotting and immunohistochemical methods. For the detection of sera possessing autoantibodies against eye muscle antigen the indirect immunosorbent assay had been used. IgA anti-eye muscle antibodies could be demonstrated in 25 cases and IgG types in 16 cases out of 40 patients. These anti-muscle autoantibodies were associated with eye muscle rather than skeletal muscle, the number of positive cases with the latter being 5/40 for IgG and 2/40 for IgA. Immunoreactive bands of IgA autoantibodies against eye cytosol were found at 84, 64, 45, 40 and 25-23 kDa in 22, 2, 16, 2 and 18 cases, respectively. A difference was observed in the staining of IgG and IgA types of autoantibodies by immunohistochemical analysis of eye muscle tissue. The IgA anti-eye muscle antibodies reacted with muscle fibers and the IgG types showed staining on endomysium. No sera of Graves' disease patients gave staining on skeletal muscle tissue. The results supported the presence of IgA anti-human eye muscle antibodies in patients with Graves' ophthalmopathy, which might play a relevant role in the development of eye disease.

Adult↗
PubMed1995

Purification and characterization of the 3-ketosteroid-delta 1-dehydrogenase of Arthrobacter simplex produced in Streptomyces lividans.

The 3-ketosteroid-delta 1-dehydrogenase (KS1DH) gene of Arthrobacter simplex IFO12069 cloned in Streptomyces lividans was overexpressed, resulting in production of the enzyme both extracellularly and intracellularly. The enzyme was purified by ammonium sulfate fractionation and chromatographies using DEAE-Toyopearl, Butyl-Toyopearl and Toyopearl HW55S from the supernatant of culture broth and cell-free extracts of S. lividans, and both preparations showed the same characteristics. The N-terminal amino acid sequence of both KS1DHs was M-D-W-A-E-E-Y-D, which coincided with the amino acid sequence deduced from the nucleotide sequence. Thus, the extracellular enzyme may derived from leakage of S. lividans cells during cultivation rather than secretion by processing of the signal sequence. The molecular weight of the enzyme was about 55,000, identical with the size deduced from the nucleotide sequence (M(r) 54,329). The optimum conditions for its activity were pH 10.0 and 40 degrees C. The enzyme catalyzed the conversion of several 3-keto-steroids, but those containing 11 alpha- or 11 beta-hydroxyl group were converted at low rates. The amino acid sequence of KS1DH from A. simplex is similar to those of KS1DH of Pseudomonas testosteroni and fumarate reductase from Shewanella putrefaciens.

Amino Acid Sequence↗
PubMed1995

Molecular cloning, expression in Streptomyces lividans, and analysis of a gene cluster from Arthrobacter simplex encoding 3-ketosteroid-delta 1-dehydrogenase, 3-ketosteroid-delta 5-isomerase and a hypothetical regulatory protein.

The Arthrobacter simplex gene coding for 3-ketosteroid-delta 1-dehydrogenase, a key enzyme in the degradation of the steroid nucleus, was cloned in Streptomyces lividans. Nucleotide sequence analysis revealed that the gene for 3-ketosteroid-delta 1-dehydrogenase (ksdD) is clustered with at least two more genes possibly involved in steroid metabolism. Upstream of ksdD, we found a gene, ksdR, encoding a hypothetical regulatory protein that shows homologies to KdgR, the negative regulator of pectin biodegradation in Erwinia, and GyIR, the activator for glycerol metabolism in Steptomyces. A helix-turn-helix DNA-binding domain can be predicted at similar positions near the N-terminal of KsdR, KdgR and GyIR. ksdl adjoining downstream to ksdD codes for a protein that has strong similarities to 3-ketosteroid-delta 5-isomerases. The highly conserved Tyr and Asp residues are present in the active-centre motif of the enzyme. The translated ksdD gene product was found to be similar to the 3-ketosteroid-delta 1-dehydrogenase of Pseudomonas testosteroni and to the fumarate reductase of Shewanella putrefaciens. A region highly conserved between the two steroid dehydrogenases can be aligned to the active-centre motif of the fumarate reductase. S. lividans strains carrying the ksdD gene overexpressed 3-ketosteroid-delta 1-dehydrogenase. The expression of 3-ketosteroid-delta 5-isomerase, however, was barely detectable in recombinant S. lividans strains carrying the ksdl gene, or in the parental Arthrobacter strain.

Amino Acid Sequence↗
PubMed1995

In vitro suppression of anti-TSH receptor antibody by autologous anti-idiotypic antibody in patients with Graves' disease.

Regulation of anti-TSH receptor antibody (anti-TSH-R antibody) in Graves' patients (n = 11) by anti-idiotypic antibody was studied using patients sera before and after one year of Methimazole treatment. Patients sera with high level of anti-TSH-R antibody (110 + 41.9 U/I) were incubated with pooled control and autologous (with low level or anti-TSH-R antibody negative) sera containing equimolar IgG G. The mixture was centrifuged and the supernatants were tested for anti-TSH-R antibodies (TRAK, Henning). It was found that the autologous sera from patients with remission were able to suppress significantly the titre of anti-TSH-R antibodies (p < 0.001), whereas the controls were capable of a less remarkable inhibition. F(ab')2 fragments of autologous IgG from remission could also suppress the levels of TSH-R antibodies. It was concluded that anti-anti-TSH-R antibodies in sera of Graves' patients might be, at least in part, responsible for inducing and maintaining remission and suppression of autoantibodies to TSH-R. It is hypothesized that the idiotype system is part of the network of natural autoantibodies and that its perturbation may give rise to pathogenetic antibodies. On the basis of this observation the autologous sera could have therapeutical implication in an accelerated remission of hyperthyroidism in Graves' disease.

Adult↗
PubMed1995

Kinetic characterization of thyroid peroxidase enzyme and its inhibition by autoantibodies.

A guaiacol method was developed to measure thyroid peroxidase (TPO) activity and the inhibitory effect of anti-TPO antibodies using purified porcine TPO. The TPO preparation was characterized kinetically and identified by western-blotting technique. The K(M) for guaiacol determined in vitro was 5.6 x 10(-4) M. Investigating the effect of IgG's from 23 hypothyroid patients on TPO activity inhibition was detected in 15 cases with the guaiacol method. It was found that anti-TPO antibodies exerted a competitive inhibition TPO activity with respect to the substrate guaiacol. The inhibition is carried by IgGF(ab')2 fragment. We wanted to gain a method which is interpreted immunologically and can be well employed in the clinical practice.

Animals↗
PubMed1993

[Successful surgical management of arterio-mesenterial duodenal compression].

A 17 year old female patient developed in 6 month a gradually exacerbating stomach passage disturbance not responding to conservative treatment. Clinical and radiological examinations verified that the compression of the duodenum was caused by irregular position of the arteria mesenterica superior. The patient was operated on and a dissection and transposition of the duodenum was performed using an end-to-end anastomosis before the arteria mesenterica superior. This method has never been seen in Hungary before. The good result of the operation was verified by the control examinations.

Adolescent↗
PubMed1993

Bacterial cholesterol oxidases are able to act as flavoprotein-linked ketosteroid monooxygenases that catalyse the hydroxylation of cholesterol to 4-cholesten-6-ol-3-one.

A new metabolite of cholesterol was found in reaction mixtures containing cholesterol or 4-cholesten-3-one as a substrate and extra- or intracellular protein extracts from recombinant Streptomyces lividans and Escherichia coli strains carrying cloned DNA fragments of Streptomyces sp. SA-COO, the producer of Streptomyces cholesterol oxidase. The new metabolite was identified as 4-cholesten-6-ol-3-one based on comparisons of its high-performance liquid chromatography, gas chromatography/mass spectrometry, infrared and proton-nuclear magnetic resonance spectra with those of an authentic standard. Genetic analyses showed that the enzyme responsible for the production of 4-cholesten-6-ol-3-one is cholesterol oxidase encoded by the choA gene. Commercially purified cholesterol oxidase (EC 1.1.3.6.) of a Streptomyces sp., as well as of Brevibacterium sterolicum and a Pseudomonas sp., and a highly purified recombinant Streptomyces cholesterol oxidase were also able to catalyse the 6-hydroxylation reaction. Hydrogen peroxide accumulating in the reaction mixtures as a consequence of the 3 beta-hydroxysteroid oxidase activity of the enzyme was shown to have no role in the formation of the 6-hydroxylated derivative. We propose a possible scheme of a branched reaction pathway for the concurrent formation of 4-cholesten-3-one and 4-cholesten-6-ol-3-one by cholesterol oxidase, and the observed differences in the rate of formation of the 6-hydroxy-ketosteroid by the enzymes of different bacterial sources are also discussed.

Biodegradation, Environmental↗
PubMed1993

[A newly developed cementless elbow joint prosthesis].

Authors describe briefly the history of the development of elbow arthroplasty. They report on their experiences with the silicone, cementless, unconstrained elbow prosthesis developed by them and implanted in 23 cases during 3 years. The prosthesis is described, the operative indication and the problems of the operative technique are reviewed. On the basis of their results and the low number of complications this method of operation is suggested first of all for the successful treatment of elbows with rheumatoid arthritis.

Arthritis, Rheumatoid↗
PubMed1992

[Incidence of intrauterine growth retardation and its significance in perinatology in Hungary].

The authors have examined the incidence of intrauterine growth retardation at a country level for the first time both in local and international aspect. Using the nomenclature of NDN-system they have found the frequency of WL-(proportional) retardation 7.95% and that of N-(disproportional) retardation 5.99%. They show incidence of retardation from county to county, as well. Examining the correlation between retardation and perinatal mortality they've stated that while the frequency of still-birth among the average developed and proportionally nutrified fetus is 0.34% and the frequency of perinatal mortality among them is 1.23%, that of the N-retardated newborns is 0.88% and 2.08%, respectively, and that of the WL-retarded is higher than the latter: 2.03% and 3.90% respectively. Regarding the incidence and mortality ratio among the two types of retardation the difference is significant.

Fetal Death↗
PubMed1992

TSH binding site structures in human eye muscle fractions identified by using covalent-crosslinking.

125I-labelled human TSH was crosslinked to the human thyroid and extraocular eye muscle membrane and cytosol fractions (which were obtained by centrifugation). Studying crosslinking of 125I-labelled TSH to the thyroid fractions, TSH binding sites' structures were demonstrated on the eye muscle membranes and in the cytosol fractions. The binding of 125I-labelled TSH was inhibited by the addition of 120 mIU/mL of unlabelled TSH (and not with 12 mIU/mL) which confirmed the presence of TSH binding sites structures (MW about 66,000 Da) on the eye muscle membrane and in its cytosol. Adding purified IgG fractions from the sera from controls and Graves' disease (with high titer of antibodies against TSH receptor) to the thyroid and eye muscle membranes and cytosol fractions, the binding of 125I-labelled human TSH was inhibited by molecular weight of about 66,000 Da in the cytosol fractions. The affinity constant of the binding sites in the human eye muscle cytosol and the number of TSH receptors were found to be 146 x 10(9) M-1 and 9.8 x 10(10) molecules/mg/mL by Scatchard analysis, respectively.

Cross-Linking Reagents↗