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At least 163 records · Page 9Linked to original sources
PubMed2001

Psychopharmacogenetics--a challenge for pharmacotherapy in psychiatry.

Differences in response to treatment or the incidence of adverse drug effects are quite common in clinical psychopharmacotherapy. Although several factors may account for these discrepancies, there is increasing knowledge that genetic factors play a major role. The aim of pharmacogenetics, a new and rapidly growing field in research, is to elucidate the variability in drug response and metabolism due to hereditary differences. According to the hypotheses on the mechanisms of drug action, several mutations in genes coding for neurotransmitter receptors, degrading enzymes, transport proteins or enzymes of the drug metabolizing system (P-450 isoenzymes) have been identified and investigated in psychiatric disorders over the last years. Although some controversy exists among the results, many studies are supportive of the hypothesis that psychopharmacogenetics will be helpful in predicting an individual patient's drug response while minimising the rate of side effects.

Chlorpromazine↗
PubMed2001

Replication protein A2 phosphorylation after DNA damage by the coordinated action of ataxia telangiectasia-mutated and DNA-dependent protein kinase.

Replication protein A (RPA, also known as human single-stranded DNA-binding protein) is a trimeric, multifunctional protein complex involved in DNA replication, DNA repair, and recombination. Phosphorylation of the RPA2 subunit is observed after exposure of cells to ionizing radiation (IR) and other DNA-damaging agents, which implicates the modified protein in the regulation of DNA replication after DNA damage or in DNA repair. Although ataxia telangiectasia-mutated (ATM) and DNA-dependent protein kinase (DNA-PK) phosphorylate RPA2 in vitro, their role in vivo remains uncertain, and contradictory results have been reported. Here we show that RPA2 phosphorylation is delayed in cells deficient in one of these kinases and completely abolished in wild-type, ATM, or DNA-PK-deficient cells after treatment with wortmannin at a concentration-inhibiting ATM and DNA-PK. Caffeine, an inhibitor of ATM and ATM-Rad3 related (ATR) but not DNA-PK, generates an ataxia-telangiectasia-like response in wild-type cells, prevents completely RPA2 phosphorylation in DNA-PKcs deficient cells, but has no effect on ataxia-telangiectasia cells. These observations rule out ATR and implicate both ATM and DNA-PK in RPA2 phosphorylation after exposure to IR. UCN-01, an inhibitor of protein kinase C, Chk1, and cyclin-dependent kinases, has no effect on IR-induced RPA2 phosphorylation. Because UCN-01 abrogates checkpoint responses, this observation dissociates RPA2 phosphorylation from checkpoint activation. Phosphorylated RPA has a higher affinity for nuclear structures than unphosphorylated RPA suggesting functional alterations in the protein. In an in vitro assay for DNA replication, DNA-PK is the sole kinase phosphorylating RPA2, indicating that processes not reproduced in the in vitro assay are required for RPA2 phosphorylation by ATM. Because RPA2 phosphorylation kinetics are distinct from those of the S phase checkpoint, we propose that DNA-PK and ATM cooperate to phosphorylate RPA after DNA damage to redirect the functions of the protein from DNA replication to DNA repair.

Androstadienes↗
PubMed2002

[Brugada syndrome].

Brugada syndrome is characterized by an ECG pattern of right bundle branch block and ST-segment elevation in right precordial leads, and sudden death caused by ventricular fibrillation(VF). The cellular basis for the syndrome is thought to be due to an outward shift in the ionic current active during phase 1 of the right ventricular epicardial action potential. Mutations of the cardiac sodium channel gene, SCN5A, have been identified as the genesis of the syndrome. This ECG pattern, which appears intermittently in most patients, is accentuated just before and after episodes of VF and is unmasked by class IA and IC antiarrhythmic agents. Development of VF is associated with an increase in vagal activity, and it occurs frequently during sleep. Implantable-cardioverter defibrillator is the effective therapy for prevention from sudden death.

Bundle-Branch Block↗
PubMedDate not supplied

A Japanese view on speciation: "Sumiwake" explosive speciation of the cichlids in Lake Victoria.

Imanishi's "mental" (cerebral) view of speciation is presented, in Mizuhata's revision. The key concept here is the "ethological partition" of the species. Members of each species=society (etho-species) share the same mental (brain) software, irrespective of their genetic structure. Cerebral animals perform active programmed selection, not to be confused with passive, non-programmed "natural selection" as in Neo-Darwinism. The program includes mating-choice of peculiar characters, distinct from the Neo-Darwinian sexual selection supposed due to the specific choosy genes. Speciation can occur, as a "partition of species=society", with bifurcation of mate-choosing program in the parent species. A main promoter for this bifurcation is species-specific "passion" for especially significant characters: long necks, ornamental antlers, ocelli feathers, bright nuptial colors etc. The cichlids in Lake Victoria achieved explosive speciation, while retaining their genetic homogeneity completely. Therefore it is illogical to attribute this divergence to extraordinary mutations in "action controlling genes". The origin of species=society (etho-species) can trace along to the Cambrian Period.

Animals↗
PubMed2005

[Resistance of Russian isolates of Neisseria gonorrhoeae to fluoroquinolones].

Fluoroquinolones still belong to the drugs of choice in the treatment of uncomplicated gonorrhea. At the same time, there have been more data on the spreading N. gonorrhoeae strains resistant to fluoroquinolones. A variety of mechanisms, like modification of the target of antibiotic's action (point mutations in genes gyrA and parC), a decreasing permeability of the bacterial cell membrane (amino-acid changes Por protein) and a growing efflux of antibiotic (mutations in the promoter or in the coding region of mtrR) mediate in the shaping resistance of the drugs. The MIC values for four fluoroquinolone-series antibiotics were determined and the gyrA, parC, por and mtrR genes were examined for resistance-responsible mutations in 32 studied clinical strains of N. gonorrhoeae. Strains with high resistance to fluoroquinolones were detected; 3 of them had no common changes in GyrA or ParC, however, amino acid changes and mutations were detected in Por protein and promoter or gene mtrR encoding region, respectively. The paper contains priority data on the detection (in Russia) of N. gonorrhoeae strains with high resistance to fluoroquinolones. Involvement of different mechanisms in the process of resistance shaping is discussed. The results are of practical importance for planning the antibacterial therapy of gonorrhoeae; they point out the need in regional testing of resistance in the N. gonorrhoeae population encountered in Russia.

Anti-Bacterial Agents↗
PubMed1988

Multiple, small exposures of far-ultraviolet or mid-ultraviolet light change the sensitivity to acute ultraviolet exposures measured by cell lethality and mutagenesis in V79 Chinese hamster cells.

Chinese hamster V79 cells (subline MI2G) were exposed repeatedly to fractionated doses of germicidal 254 nm light (far-uv) at 6 J.m-2/fraction/day or sunlight-simulating 290-330 nm (mid-uv) at 150 J.m-2/fraction/day and sensitivities to cell killing action and mutation of far-uv and mid-uv were examined. As the number of exposure fractions increased, the cell cultures became resistant to cell killing induced by both far-uv and mid-uv. Increases in both Do and Dq were observed. Treatment with exposures of 6 J.m-2 far-uv is more efficient in yielding cell cultures that are resistant than exposures of 150 J.m-2 mid-uv. In contrast to the cells exposed to repeated far-uv, the cells exposed to repeated mid-uv were relatively more resistant to cell killing effects of mid-uv than far-uv, suggesting a possible role of photolesions other than pyrimidine dimers. When mutants resistant to 6-thioguanine were assayed during repeated exposure to far- or mid-uv light, the yield was initially linear with accumulating dose. At high total accumulated doses, the frequency decreased gradually (6 J.m-2 mid-uv) or reached a plateau (150 J.m-2 mid-uv). The sensitivity of N80 cells (exposed to 80 fractions of mid-uv) to mutation induction by uv light is higher than that of the original MI2G cells, whereas U81 cells (exposed to 81 fractions of far-uv) have a sensitivity similar to that of the original cells. Although an initial decrease in resistance to cell killing was observed, resistant cells retained their characteristics after 100 days in culture without further exposure. Cross-resistance to X rays was not shown. The data in this paper suggest that the capacity for repair of photolesions in DNA by repair processes was enhanced in cell cultures by repeated exposure to far-uv or mid-uv and that this altered the cells' ability to cope with lethal and mutagenic lesions. It remains to be seen if these changes in cell sensitivity were brought about by selective or inductive processes or a combination of both.

Animals↗
PubMed1984

[Pedigree in which multiple pregnancy is combined with sterility].

A case of simultaneous hereditary transmission of twinning and sterility in a jewish family from Novosibirsk is described. The both characters are transmitted by male and female. It is suggested that twinning and sterility are connected with the action of one dominant mutation with multiple pleiotropic action on propagation system. The action of two alleles in homozygotes is additive. The importance of special search for and study of similar situations for understanding mechanisms of twinning and sterility occurrence in man is discussed.

Abortion, Spontaneous↗
PubMed1999

Genetic polymorphisms and ethnic admixture in African-derived black communities of northeastern Brazil.

Unrelated individuals from 3 relatively isolated African-derived communities in the state of Piauí, northeastern Brazil, and blood donors from Teresina (admixed population), the capital city of Piauí, were analyzed for the ESD, CA2, GC, HP, GLO1, PGM1, HB, ACP1 protein loci and for the VWF1 and VWF2 short tandem repeat (STR) loci. As expected, high frequencies of alleles considered characteristics of African populations were detected. The VWF1 allele distribution was bi-modal, whereas the VWF2 distribution was unimodal, suggesting differential action of mutation and selection factors in the 2 STRs despite their close location on the same gene. The genetic distances between the Brazilian isolates coincide with their geographic distances. The ethnic admixture estimated by a maximum-likelihood method showed African, European, and Amerindian components of 61%, 17%, and 22% for Mimbó, 72%, 12%, and 16% for Sítio Velho, and 31%, 21%, and 48% for Teresina, respectively.

Africa↗
PubMed2003

Mutational analysis of molecular requirements for the actions of general anaesthetics at the gamma-aminobutyric acidA receptor subtype, alpha1beta2gamma2.

BACKGROUND: Amino acids in the beta subunit contribute to the action of general anaesthetics on GABA(A) receptors. We have now characterized the phenotypic effect of two beta subunit mutations in the most abundant GABA(A) receptor subtype, alpha1beta2gamma2. RESULTS: The beta2(N265M) mutation in M2 decreased the modulatory actions of propofol, etomidate and enflurane, but not of alphaxalone, while the direct actions of propofol, etomidate and alphaxalone were impaired. The beta2(M286W) mutation in M3 decreased the modulatory actions of propofol, etomidate and enflurane, but not of alphaxalone, whereas the direct action of propofol and etomidate, but not of alphaxalone, was impaired. CONCLUSIONS: We found that the actions of general anaesthetics at alpha1beta2(N265M)gamma2 and alpha1beta2(M286W)gamma2 GABA(A) receptors are similar to those previously observed at alpha2beta3(N265M)gamma2 and alpha2beta3(M286W)gamma2 GABA(A) recpetors, respectively, with the notable exceptions that the direct action of propofol was decreased in alpha1beta2(M286W)gamma2 receptors but indistinguishable form wild type in alpha2beta3(M286W)gamma2 receptors and that the direct action of alphaxalone was decreased in alpha1beta2(N265M)gamma2 but not alpha2beta3(N265M)gamma2 receptors and indistinguishable form wild type in alpha1beta2(M286W)gamma2 receptors but increased in alpha2beta3(M286W)gamma2 receptors. Thus, selected phenotypic consequences of these two mutations are GABA(A) receptor subtype-specific.

Anesthetics, General↗
PubMed1997

Telomerase RNA mutations in Saccharomyces cerevisiae alter telomerase action and reveal nonprocessivity in vivo and in vitro.

The ribonucleoprotein enzyme telomerase adds telomeric DNA to chromosomal ends. In most eukaryotes the telomeric repeat units are repeated precisely, consistent with the action of a telomerase that faithfully copies its RNA template. In contrast, Saccharomyces cerevisiae telomeric repeats are degenerate, suggesting that its telomerase has unusual mechanistic properties. We mutated the S. cerevisiae telomerase RNA (TLC1) with a series of 3-base (GUG) substitutions in and next to the 17-nucleotide templating domain. All mutant telomerases were active in TLC1/tlc1 diploids and synthesized patterns of mixed wild-type and mutant telomeric repeats into telomeric DNA, consistent with nonprocessive action. Telomerase isolated from cells containing each mutated tlc1 allele by itself had altered reaction properties in vitro. One mutant template enzyme, 476GUG, was active in vivo and in vitro in the presence of wild-type TLC1 RNA but lacked detectable activity in its absence. Haploid tlc1-476GUG cells containing only this mutant tlc1 allele underwent senescence. Other tlc1 template region mutations allowed maintenance of shortened telomeres in vivo but altered specific enzymatic properties of telomerase in vitro, including induction of primer-template slippage (472GUG) or alteration of the 5' boundary of the template (467GUG). These data demonstrate that telomerase RNA bases influence enzyme activity profoundly, suggesting that their roles are not confined to serving simply as the template for this specialized reverse transcriptase.

Base Sequence↗
PubMed2005

Effects of Kv1.1 channel glycosylation on C-type inactivation and simulated action potentials.

Kv1.1 channels are brain glycoproteins that play an important role in repolarization of action potentials. In previous work, we showed that lack of N-glycosylation, particularly lack of sialylation, of Kv1.1 affected its macroscopic gating properties and slowed activation and C-type inactivation kinetics and produced a depolarized shift in the steady-state activation curve. In our current study, we used single channel analysis to investigate voltage-independent C-type inactivation in both Kv1.1 and Kv1.1N207Q, a glycosylation mutant. Both channels underwent brief and long-lived closures, and the lifetime and frequency of the long-lived closed states were voltage-independent and similar for both channels. We found that, as in macroscopic measurements, Kv1.1N207Q exhibited a approximately 8 mV positive shift in its single channel fractional open time (fo) and a shallower fo-voltage slope compared with Kv1.1. Data suggested that C-type inactivation reflected the equilibration time with at least two slow voltage-independent long-lived closed states that followed the rapid activation process. In addition, data simulation indicated that the C-type inactivation process reflected the equilibration time between the open state and at least two long-lived closed states. Moreover, the faster macroscopic current decay in Kv1.1 mostly reflected a slower equilibration time in these channels as compared with Kv1.1N207Q. Finally, action potential simulations indicated that the N207Q mutation broaden the action potential and decreased the interspike interval. The shape of the action potential was not significantly affected by C-type inactivation, however, for a given channel, C-type inactivation increased the interspike interval. Data and simulations suggested that excitable cells could use differences in K(+) channel glycosylation degree as an additional mechanism to increase channel functional diversity which could modify cell excitability.

Action Potentials↗