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Biomedical subjects

A Tolun

Publications and source records attributed to A Tolun.

At least 19 recordsLinked to original sources
PubMed1998

Evidence for the presence of muscarinic M2 and M4 receptors in guinea-pig gallbladder smooth muscle.

1. The affinities of 10 selective muscarinic receptor antagonists against [3H]-quinuclidinyl benzilate (QNB) binding were determined to characterize the muscarinic receptors present in guinea-pig gallbladder smooth muscle. The highest correlation was obtained for the comparison between the pKi values for the gallbladder smooth muscle and M2 sites. Pirenzepine revealed two binding sites with affinities indicating the presence of muscarinic M2 receptors in abundance and a minor population of an additional site(s). 2. Carbachol produced gallbladder contractions, stimulated phosphoinositide (PI) hydrolysis and inhibited cAMP formation concentration-dependently with pD2 values of 6.12 +/- 0.11, 5.18 +/- 0.33 and 7.19 +/- 0.15, respectively. 3. Pirenzepine, 4-DAMP, HHSiD, pF-HHSiD, AF-DX 116, methoctramine, AQ-RA 741, guanylpirenzepine and AF-DX 384 showed competitive antagonism against carbachol-induced gallbladder contractions. There was no correlation between the pA2 values for the gallbladder and pKi values for the M2 sites, whereas significant correlations were found for the M1, M3 and M4 sites, the best correlation being between the pA2 values for the gallbladder and M4 subtypes. 4. Finally, the presence of both m2 and m4 receptor proteins were demonstrated by Western blot analysis. It is concluded that guinea-pig gallbladder smooth muscle has both muscarinic M2 and M4 receptors, which are coupled to adenylate cyclase inhibition and PI hydrolysis. 5. Although it seems likely that M2 receptors do not play a primary role in carbachol-induced guinea-pig gallbladder contraction, the characterization of the muscarinic subtypes which mediate these contractile responses needs further evidence.

Adenylyl Cyclases↗
PubMed1996

From Asia to Europe: mitochondrial DNA sequence variability in Bulgarians and Turks.

Two hypervariable sequence segments in the control region of mitochondrial DNA were determined in samples of Bulgarians and Turks. The Turkish sample presented a higher degree of internal diversity, in terms of total number of variable nucleotides, as well as in the average pairwise nucleotide difference. Pairwise difference distributions were built for both samples, yielding smooth bell shapes in agreement with the Rogers and Harpending model. The Bulgarian and Turkish data were compared with several European and W. Asian Caucasoid populations (Basques, Tuscans, Sardinians, British, Middle Easterners and Indians). Mean pairwise differences suggest that a demographic expansion occurred sequentially in the Middle East, through Turkey, to the rest of Europe (Bulgaria included). Current mutation rate estimates date this expansion in times ranging between 50,000 and 100,000 years ago and, thus, would correspond to the arrival of anatomically modern humans in Europe. Sequence trees for segment I show that European and Middle Eastern sequences derived from the reference sequence. Coalescence times for segment I sequences agree with those predicted by pairwise distributions. Genetic trees were constructed between populations and revealed an extreme homogeneity between European samples.

Base Sequence↗
PubMed1996

A high frequency of distinct ATM gene mutations in ataxia-telangiectasia.

The clinical features of the autosomal recessive disorder ataxia-telangiectasia (AT) include a progressive cerebellar ataxia, hypersensitivity to ionizing radiation, and an increased susceptibility to malignancies. Epidemiological studies have suggested that AT heterozygotes may also be at increased risk for malignancy, possibly as a consequence of radiation exposure. A gene mutated in AT patients (ATM) has recently been isolated, making mutation screening in both patients and the general population possible. Because of the relatively large size of the ATM gene, the design of screening programs will depend on the types and distribution of mutations in the general population. In this report, we describe 30 mutations identified in a panel of unrelated AT patients and controls. Twenty-five of the 30 were distinct, and most patients were compound heterozygotes. The most frequently detected mutation was found in three different families and had previously been reported in five others. This corresponds to a frequency of 8% of all reported ATM mutations. Twenty-two of the alterations observed would be predicted to lead to protein truncation at sites scattered throughout the molecule. Two fibroblast cell lines, which displayed normal responses to ionizing radiation, also proved to be heterozygous for truncation mutations of ATM. These observations suggest that the carrier frequency of ATM mutations may be sufficiently high to make population screening practical. However, such screening may need to be done prospectively, that is, by searching for new mutations rather than by screening for just those already identified in AT families.

Ataxia Telangiectasia↗
PubMed1994

Cystic fibrosis patients from the Black Sea region: the 1677delTA mutation.

A 2 bp deletion in exon 10 of the CFTR gene, 1677delTA, which is very rare among CF chromosomes worldwide, was found to be a relatively common cause of cystic fibrosis in countries located in the region of the Black Sea. The frequency of the mutation was compared among cystic fibrosis patients from several populations, namely Bulgarians, Turks, Greek-Cypriots, Georgians, and Russians. The deletion is most common among Georgian CF patients and gradually declines in frequency in neighbouring populations. It is invariably related to a common polymorphic haplotype which is rare among normal chromosomes in Bulgaria but was found to be common in Turkey. The geographic gradient in the frequency of the mutation, along with findings on polymorphic haplotype distribution, suggest that the mutation is relatively young in evolutionary terms and spread as the result of west and south-bound migrations originating from Georgia. The 1677delTA mutation is related to a severe clinical phenotype with a high early mortality rate among homozygotes and possibly to an increased risk of meconium ileus.

Bulgaria↗
PubMed1994

Dinucleotide repeat polymorphism at 11q23.

A highly polymorphic CA repeat sequence was identified near the NCAM gene on chromosome 11q23. It should be a useful marker in the localization of genes responsible for neurological disorders that are known to map to this region.

Base Sequence↗
PubMed1992

The molecular basis of beta-thalassemia in Turkey.

By using oligonucleotide hybridization, restriction endonuclease analysis and direct sequencing of amplified genomic DNA, we have been able to characterize 18 different mutations in the beta-globin genes of 161 beta-thalassemia homozygotes and 107 beta-thalassemia heterozygotes from Turkey (429 beta-thalassemia chromosomes). Previous studies dealing with beta-thalassemia in Mediterranean countries have shown that, in most Mediterranean populations, only a few mutations are prevalent. In contrast, beta-thalassemia in Turkey does not seem to be associated with a few predominant mutations. The six most frequent alleles, IVS-I-110 (G----A), IVS-I-6(T----C), FSC-8 (-AA), IVS-I-1(G----A), -30(T----A) and FSC-5 (-CT), account for only 69.3% of the disease genes; indeed, all 26 mutations assayed represent 85.8% of the disease genes, confirming the considerable molecular heterogeneity of beta-thalassemia among Turks, and indicating the possible presence of rare, previously undefined, mutations in the population. Two mutations observed in this study, IVS-I-116 (T----G) and Cd44(-C), have not been reported in the Turkish population to date. Since preventive medical services, such as genetic counseling and prenatal diagnosis, are greatly improved by detailed knowledge of the molecular pathology of beta-thalassemia, we strongly believe that the presented data will facilitate the intended establishment of a prenatal diagnosis center, based on DNA analysis, in Turkey.

Alleles↗
PubMed1992

DNA analysis in Turkish Duchenne/Becker muscular dystrophy families.

The molecular genetics of Duchenne/Becker muscular dystrophy was investigated in 81 affected Turkish families. Deletions were detected by multiplex polymerase chain reaction assays and cDNA Southern analyses. The distribution of the deletions along the gene and their correlation to clinical phenotype were different from the studies reported on other populations. Moreover, DNA polymorphisms in mothers were determined using 8 DNA probes and three CA repeat sequences, and a high degree of informativeness was observed.

Chromosome Deletion↗
PubMed1992

Ataxia-telangiectasia: linkage analysis of chromosome 11q22-23 markers in Turkish families.

To further pinpoint the location of the genes for ataxia-telangiectasia on the long arm of chromosome 11, we performed linkage analysis and analysis of recombinants of genetic haplotypes on 14 Turkish families with ataxia-telangiectasia, 12 of which were consanguineous. These studies used more than 25 polymorphic genetic markers spanning a region of the long arm of chromosome 11 that is larger than 50 cM. Seven markers gave significant LOD scores to AT: CJ5, DRD2, CJ208, S144, CD3E, PBGD, and S147, as did haplotypes created with pairs of markers DRD2/CJ5 and S144/CJ208, giving recombination fractions (theta) of 0.00, 0.00, 0.05, 0.08, 0.03, 0.09, 0.07, 0.00, and 0.06, respectively. Monte Carlo analysis of these 14 Turkish families indicated the best location for a single AT gene to be within a 6 cM sex-averaged (3 cM male-specific) interval defined by STMY and CJ77; this was three times more likely than the next most likely location (peak III) at the DRD2 locus. The analysis also revealed a peak (peak II) between S147 and S133, which may represent the complementation group D gene. Recombinant analysis of haplotypes also localized an AT locus to the STMY-CJ77 interval. Taken together, these results suggest that at least two distinct AT loci exist (ATA and ATD) at 11q22-23, with perhaps a third locus, ATC, located very near to the ATA gene. This genetic heterogeneity further complicates plans to isolate the major ATA and ATC genes and to begin identifying AT carriers in the general population.

Ataxia Telangiectasia↗
PubMed1991

Localization of an ataxia-telangiectasia locus to a 3-cM interval on chromosome 11q23: linkage analysis of 111 families by an international consortium.

Linkage of at least two complementation groups of ataxia-telangiectasia (AT) to the chromosomal region 11q23 is now well established. We provide here an 18-point map of the surrounding genomic region, derived from linkage analysis of 40 CEPH families. On the basis of this map, 111 AT families from Turkey, Israel, England, Italy, and the United States were analyzed, localizing the AT gene(s) to an 8-cM sex-averaged interval between the markers STMY and D11S132/NCAM. A new Monte Carlo method for computing approximate location scores estimates this location as being at least 10(8) times more likely than the next most likely interval, with a support interval midway between STMY and D11S132 that is either 5.2 cM (sex-averaged and conservatively based on 3 lod scores from the maximum-location score) or 2.8 cM (male specific, based on a 2.72:1 interval-specific female-to-male distance ratio.

Ataxia Telangiectasia↗
PubMed1986

Analysis of fragile X-mental retardation families using flanking polymorphic DNA probes.

Fragile-X mental retardation (FRAX-MR) is one of the more common X-linked disorders affecting 1 in 1,500 newborn males. This disease is characterized by the expression of fragile site in the region q27.3 of the X-chromosome of affected boys when their lymphocytes are cultured in folate deficient medium. In most patients there is macroorchidism postpubertally. The clinical diagnosis of carrier females based on the expression of fragile site in Xq27.3 is usually difficult and sometimes impossible. About half of the carrier females escape diagnosis by this method. Furthermore, prenatal diagnosis is not always feasible. Using Restriction Fragment Length Polymorphism (RFLP) and cloned DNA segments from the region Xq27-Xqter as probes, we have investigated Swedish families with FRAX-MR in three generations. Interesting observations, previously unreported to our knowledge, have been made in some patients and carrier mothers, using one of the probes which is localized to the distal end of Xq. The significance of these findings and the linkage of the disease locus to the different probes used in this study is presented.

DNA↗
PubMed1982

Separation of the minimal replication region of the F plasmid into a replication origin segment and a trans-acting segment.

An analysis was carried out on the replication functions within a 2.3 kilobase (kb) segment of the F plasmid which contains an origin (ori s) of replication and is capable of autonomous replication in Escherichia coli. Two separable regions were delineated for this segment: an origin region of approximately 1,140 bp in length and a segment of approximately 1,140 bp that functions in trans to support replication of the origin region. The trans-acting segment is functional as part of an F replicon or when inserted into the E. coli chromosome. A prominent feature of the trans-acting segment is a coding sequence for a 29 K protein (Murotsu et al. 1981).

DNA Replication↗
PubMed1981

Direct repeats of the F plasmid incC region express F incompatibility.

The nucleotide sequence of the incompatibility region incC, located at 45.8--46.4 kb on the F plasmid map, was determined. This region consists of 543 bp and contains sufficient information to code for only two small polypeptides of 34 and 30 amino acids each. Deletion of the ATG start codons for these two polypeptides has no effect on expression of incC incompatibility. A prominent feature of this sequence is the presence of five 22 bp direct repeats. A 58 bp segment of the incC region that contains two of these direct repeats was inserted into plasmid pACYC184, which is compatible with the F plasmid. The pACYC184 plasmid containing the direct-repeat sequences now expresses incompatibility with the F'lac plasmid and replication-proficient derivatives of the mini-F plasmid.

Bacterial Proteins↗
PubMed1979

Purification of RNA-DNA hybrids by exclusion chromatography.

A simple method for selection of RNA-DNA hybrids has been developed and applied to the purification of adenovirus-specific messenger RNA. Cytoplasmic RNA prepared from adenovirus type 2 (ad2)-infected HeLa cells or from an ad2-transformed rat cell line was hybridized in solution to the complementary strands of ad2 DNA. The hybridization mixture was subsequently fractionated by chromatography on a Sepharose 2B column. The intact probe DNA as well as the RNA-DNA hybrids are excluded from the gel matrix and elute with the void volume. Nonhybridized RNA, in contrast, is included into the gel matrix and elutes as a broad peak well separated from the excluded fractions. Fractions corresponding to the void volume, were collected and the RNA-DNA hybrids were denatured in 90% formamide. The selected RNA was separated from the DNA by affinity chromatography on poly(U)-Sepharose. Restriction endonuclease fragments of DNA with a large enough size to make them excluded from the agarose column were also used for hybridization. In these experiments hybridizations were carried out under conditions which would allow R-loop formation (Thomas, M., White, R.L., and Davis, R.W. (1976) Proc. Natl. Acad. Sci. U.S.A. 73, 2294-2298) and the hybridized RNA was separated from unhybridized RNA by Sepharose chromatography. The validity of the method was demonstrated by programming an in vitro protein-synthesizing system with selected RNA.

Adenoviruses, Human↗
PubMed1979

Sequence of inverted terminal repetitions from different adenoviruses: demonstration of conserved sequences and homology between SA7 termini and SV40 DNA.

We have established the nucleotide sequence for the inverted terminal repetition of human adenovirus type 3, a subgroup B adenovirus. The repetition, which is 136 bp long, shows a high degree of homology with the known sequence for the inverted repetition of adenovirus type 5 (Steenbergh et al., 1977) a subgroup C adenovirus. Partial sequence information convering 120 bp of the inverted terminal repetitions of human serotype 12, a subgroup A member, and of simian adenovirus type 7 has also been obtained. A comparison of the established sequences shows that the terminal repetitions, in particular the first 50 bp from the ends, contain sequences that have been well conserved in adenovirus evolution. For instance, only six mismatched base pairs were detected among the first 50 bp in the repetitions of simian adenovirus type 7 and human adenovirus type 5, although the homology between simian adenovirus 7 and human subgroup C adenoviruses was estimated to be only 30%. A 14 bp sequence located 9-22 nucleotides from the ends is present in DNAs from all the human serotypes examined as well as in simian adenovirus 7 DNA. Furthermore, the simian adenovirus 7 repetition contains a 21 bp sequence which is present in SV40 DNA, close to the origin of DNA replication.

Adenoviridae↗
PubMed1976

Two complementary strand-specific termination sites for adenovirus DNA replication.

Adenovirus type 2 DNA, specifically labeled at the termini for DNA replication, was prepared by isolation of viral DNA molecules which were completed during short pulses with 3H-thymidine. The distribution of radioactivity in the two complementary strands at the termini for DNA replication was determined by liquid phase hybridization and gelelectrophoresis. At the right-hand terminus, nearly all radioactivity was found in the viral h strand, whereas at the left-hand terminus, most radioactivity was confined to the viral l strand. The results suggest that both molecular ends serve as origins and termini for replication of adenovirus type 2 DNA.

Adenoviridae↗