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Results for “variable methylation”

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PubMed2002

The interactions of cyanobacterial cytochrome c6 and cytochrome f, characterized by NMR.

During oxygenic photosynthesis, cytochrome c(6) shuttles electrons between the membrane-bound complexes cytochrome bf and photosystem I. Complex formation between Phormidium laminosum cytochrome f and cytochrome c(6) from both Anabaena sp. PCC 7119 and Synechococcus elongatus has been investigated by nuclear magnetic resonance spectroscopy. Chemical-shift perturbation analysis reveals a binding site on Anabaena cytochrome c(6), which consists of a predominantly hydrophobic patch surrounding the heme substituent, methyl 5. This region of the protein was implicated previously in the formation of the reactive complex with photosytem I. In contrast to the results obtained for Anabaena cytochrome c(6), there is no evidence for specific complex formation with the acidic cytochrome c(6) from Synechococcus. This remarkable variability between analogous cytochromes c(6) supports the idea that different organisms utilize distinct mechanisms of photosynthetic intermolecular electron transfer.

Cyanobacteria↗

PubMed2003

Treatment of secondary hyperparathyroidism by high calcium diet is associated with enhanced resistance artery relaxation in experimental renal failure.

BACKGROUND: Vasorelaxation is impaired in renal failure (RF) and hypertension. A high calcium diet enhances vasodilatation and reduces blood pressure in experimental hypertension. Oral calcium salts are used as phosphate binders in RF. However, the effect of increased calcium intake on arterial tone in RF is unknown. METHODS: We investigated the influence of an 8-week high calcium diet (0.3 vs 3.0%) on resistance artery tone in 5/6 nephrectomized (NTX) rats. Calcium was supplemented as carbonate salt, blood pressure measured by tail-cuff, urine collected in metabolic cages, and samples taken for blood chemistry and parathyroid hormone (PTH). Functional studies of isolated third-order branches of the mesenteric artery in vitro were performed using the Mulvany multimyograph. RESULTS: Plasma urea was elevated 1.6-fold and systolic blood pressure by 10 mmHg after NTX, while increased calcium intake was without effect on these variables. Plasma PTH and phosphate were raised following NTX, and suppressed by high calcium diet. Vasorelaxations induced by K(+) channel agonists 11,12-epoxyeicosatrienoic acid and levcromakalim were impaired after NTX. Vasorelaxation induced by acetylcholine was also reduced following NTX, and experiments with N(G)-nitro-L-arginine methyl ester, diclofenac and charybdotoxin + apamin suggested that the K(+) channel-mediated component of endothelium-dependent relaxation was deficient after NTX. Increased calcium intake corrected all impairments of vasodilatation in NTX rats. CONCLUSIONS: Deficient vasorelaxation via K(+) channels was normalized by high calcium diet in experimental RF. This effect was independent of the degree of renal impairment and blood pressure, but was associated with improved calcium metabolism: plasma levels of PTH and phosphate were decreased and ionized calcium was increased.

Animals↗

PubMed1983

Cardiovascular responses of rats to intrahypothalamic injection of carbachol and noradrenaline.

Carbachol (0.1-2 micrograms) and noradrenaline (5-20 micrograms) injected into the anterior hypothalamus of unanaesthetized unrestrained rats evoked dose-dependent falls in heart rate and increases in arterial blood pressure. When the above amine injections were repeated in rats anaesthetized with chloral hydrate, sodium pentobarbitone or halothane the evoked bradycardias were usually smaller and the changes in arterial blood pressure more variable. The cardiovascular responses to carbachol (1 microgram) and to noradrenaline (10 micrograms) were antagonized by intrahypothalamic injection of atropine (1 microgram) and phentolamine (10 micrograms), respectively. The bradycardias evoked by carbachol (1 microgram) and by noradrenaline (10 micrograms) were abolished by pretreatment with intra-arterial injection of methyl atropine (100 micrograms 100 g-1). The hypertensive responses to carbachol (1 microgram) and to noradrenaline (10 micrograms) were reduced by pretreatment with intra-arterial injection of thymoxamine (500 micrograms 100 g-1).

Anesthesia↗

PubMed1984

Chronic lability of the arterial blood pressure produced by electrolytic lesions of the nucleus tractus solitarii in the rat.

The purpose of this study was to assess the chronic effects of lesions of the nucleus tractus solitarii on the cardiovascular activity of rats. Arterial pressure and heart rate were recorded in conscious, unrestrained rats 7-216 days following placement of electrolytic lesions in the nucleus tractus solitarii. To assess the impact of environmental stimuli on the mean level and lability of the mean arterial pressure, cardiovascular activity was recorded under conditions of controlled and uncontrolled environmental stimulation. Nucleus tractus solitarii lesions abolished the reflex bradycardia to a phenylephrine-induced elevation in arterial pressure. A marked increase in the lability of the mean arterial pressure was produced with nucleus tractus solitarii lesions. The standard deviation of the mean arterial pressure, an index of lability, was 380% greater in rats with lesions than in control rats. The average mean arterial pressure, heart rate and heart rate variability were not significantly different between the lesion and control groups, regardless of the environmental conditions under which the measurements were made. Nucleus tractus solitarii lesions also greatly exaggerated the arterial pressure response to naturally occurring behaviors, such as eating and drinking. Vagal and beta-adrenergic blockade with methyl atropine and propranolol did not alter the average level or lability of the mean arterial pressure, although heart rate responses were similar in both groups. alpha-Receptor blockade with prazosin significantly lowered the mean arterial pressure in both lesion and control rats, but the decrease in mean arterial pressure was significantly greater in rats with nucleus tractus solitarii lesions (42 +/- 6 mm Hg, 38.5%) than in control rats (27 +/- 4 mm Hg, 23.2%). Prazosin also reduced the lability of the mean arterial pressure to control levels in rats with lesions. Thus, the chronic effects of nucleus tractus solitarii lesions in rats are to abolish the cardiomotor component of the baroreflexes and to produce extreme lability of the arterial pressure without altering the average level of the mean arterial pressure. Exaggerated blood pressure responses are seen in association with various behaviors. These effects are mediated primarily by changes in sympathetic discharge to the vasculature and are independent of the ambient level of environmental stimuli.

Animals↗

PubMed1991

Formulary evaluation of second-generation cephamycin derivatives using decision analysis.

Use of decision analysis in the formulary evaluation of the second-generation cephamycin derivatives cefoxitin, cefotetan, and cefmetazole is described. The rating system used was adapted from one used for the third-generation cephalosporins. Data on spectrum of activity, pharmacokinetics, adverse reactions, cost, and stability were taken from the published literature and the FDA-approved product labeling. The weighting scheme used for the third-generation cephalosporins was altered somewhat to reflect the more important aspects of the cephamycin derivatives and their potential role in surgical prophylaxis. Sensitivity analysis was done to assess the variability of the final scores when the assigned weights were varied within a reasonable range. Scores for cefmetazole and cefotetan were similar and did not differ significantly after sensitivity analysis. Cefoxitin scored significantly lower than the other two drugs. In the absence of data suggesting that the N-methyl thiotetrazole side chains of cefmetazole and cefotetan cause substantial toxicity, these two drugs can be considered the most cost-efficient members of the second-generation cephamycins.

Bacterial Infections↗

PubMed1990

A transgene insertional mutation at an imprinted locus in the mouse genome.

Genetic imprinting in mice results in functional differences in the oocyte and spermatocyte genomes, as evidenced by both genetic and pronuclear transfer experiments. To gain insights into the molecular mechanisms involved in the imprinting process, researchers have studied methylation phenotypes and expression of hemizygous transgenes associated with parental origin. In this report, we describe a transgenic mouse lineage in which expression of both the transgene and an endogenous gene at the insertion site are determined by the parent of origin. The mutation caused by transgene insertion shows variable expressivity and incomplete penetrance in addition to a modified dominant pattern of inheritance.

Animals↗

PubMed1990

Antimyoclonic effect of MK-801: a possible role for NMDA receptors in developmental myoclonus of the neonatal rat.

Rat pups exhibit transient "developmental dyskinesias," such as tremor and myoclonus, that are analogous to motor immaturities of the human neonate. Myoclonic jerks in the neonatal rat may reflect a developmental imbalance of excitatory and inhibitory neurotransmission. To test this hypothesis, spontaneous myoclonic jerks of naive rat pups (n = 200) were characterized behaviorally and pharmacologically. The frequency of myoclonus was high (154 +/- 14 jerks/30 min) in the first week. The distribution of jerks included limbs (47%) (27% in forelimbs and 20% in hindlimbs), tail (30%), trunk (12%), and head (11%). Myoclonus constituted the predominant neonatal adventitious movement (81%). Myoclonic jerks were variable in intensity, focal and multi-focal more often than generalized, and occurred when nonrespiratory movements were infrequent or absent, suggesting sleep. Myoclonic frequency significantly diminished after the second week; therefore, drug effects were studied in the first 7 days. Systemic injection of the novel noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 blocked neonatal myoclonus in a dose-dependent manner (ID50 = 0.67 mg/kg; r = 0.93). The nonselective excitatory amino acid (EAA) receptor antagonist kynurenic acid was ineffective. The EAA antagonist AP4 (1 and 10 mg/kg) also reduced myoclonic jerks, but other drugs, such as the selective glycine antagonist Iso-THAO (1 and 10 mg/kg), strychnine (0.5 mg/kg), clonazepam, and diazepam (1 mg/kg), were ineffective blockers. The putative agonists quisqualic acid (1-50 mg/kg) and NMDA (1-10 mg/kg) altered myoclonus only at behaviorally toxic doses. These data suggest that EAA receptors participate in developmental myoclonus of the neonatal rat and that development myoclonus may be a useful quantitative model of functional maturity of excitatory/inhibitory synapses. The efficacy of MK-801 also should be evaluated in drug- and lesion-induced myoclonus. Recognition of the high frequency and state dependence of spontaneous myoclonic jerks in neonatal rats may be important to neonatal antiepileptic drug studies.

Aminobutyrates↗

PubMed1991

Influence of genome imprinting on gene expression, phenotypic variations and development.

Genome imprinting confers functional differences on parental chromosomes as a result of the differences in epigenetic inheritance from parental germlines. Repressed and derepressed chromatin structures probably constitute the initial germline-dependent 'imprints'. Any subsequent modifications, such as DNA methylation, will be influenced by these initial epigenetic modifications. Hence, epigenetic modifications of parental alleles probably occur progressively and this will affect their potential for expression. It appears that imprinting of some parental alleles is critical for their dosage, affecting embryonic growth, cell proliferation and differentiation. Genetic studies highlight the influence of subsets of imprinted genes and identify those which are crucial for development. Genomic imprinting also affects some transgene loci and dominant mutations with accompanying variable penetrance and expressivity. The response of transgenes can be influenced by modifier genes whose presence is most readily detected in different inbred backgrounds. The influence of modifier genes can in turn be affected by their parental origin, perhaps partly by the maternally inherited oocyte cytoplasmic factors, as well as by complex interactions between some parental alleles and oocyte cytoplasmic factors. The resulting epigenetic modifications of unlinked loci can result in substantial phenotypic variations.

Animals↗

PubMed1998

Effect of nitric oxide synthase inhibitor on diaphragmatic function after resistive loading.

We studied the effect of a nitric oxide synthase inhibitor, Nomega-Nitro-L-arginine-methyl-ester (L-NAME), on in vitro diphragmatic function both at rest (control) or after inspiratory resistive loading (IRL). Sprague-Dawley rats were anesthetized, instrumented, and then the following experimental groups: (1) controls; (2) L-NAME (100 mg/kg/body weight intravenously alone); (3) IRL alone; and (4) L-NAME + IRL. The IRL protocol consisted of applying a variable resistor to the inspiratory limb of a two-way valve at 70% of maximal airway pressure until apnea. After the experiment, the animals were sacrificed and diaphragmatic strips were obtained for activity of constitutive nitric oxide synthase (cNOS) and measurements of in vitro contractile properties: tetanic (Po) and twitch tensions (Pt). cNOS activity was significantly decreased in the L-NAME and L-NAME + IRL groups (P < or = 0.05) as compared with control and IRL groups. L-NAME alone did not affect Po or Pt. However, in both IRL groups, with and without was a significant decrease in Po and Pt. This reduction was comparable in both groups. In summary, our data showed that L-NAME resulted in a significant decrease cNOS activity, but in vitro contractility was impaired.

Animals↗

PubMed2001

Assessing the reliability of PBPK models using data from methyl chloride-exposed, non-conjugating human subjects.

Physiologically based pharmacokinetic (PBPK) models are often optimized by adjusting metabolic parameters so as to fit experimental toxicokinetic data. The estimates of the metabolic parameters are then conditional on the assumed values for all other parameters. Meanwhile, the reliability of other parameters, or the structural model, is usually not questioned. Inhalation exposures with human volunteers in our laboratory show that non-conjugators lack metabolic capacity for methyl chloride entirely, and that elimination in these subjects takes place via exhalation only. Therefore, data from these methyl chloride exposures provide an excellent opportunity to assess the general reliability of standard inhalation PBPK models for humans. A hierarchical population PBPK model for methyl chloride was developed. The model was fit to the experimental data in a Bayesian framework using Markov chain Monte Carlo (MCMC) simulation. In a Bayesian analysis, it is possible to merge a priori knowledge of the physiological, anatomical and physicochemical parameters with the information embedded in the experimental toxicokinetic data obtained in vivo. The resulting estimates are both statistically and physiologically plausible. Model deviations suggest that a pulmonary sub-compartment may be needed in order to describe the inhalation and exhalation of volatile adequately. The results also indicate that there may be significant intra-individual variability in the model parameters. To our knowledge, this is the first time that the toxicokinetics of a non-metabolized chemical is used to assess population PBPK parameters. This approach holds promise for more elaborate experiments in order to assess the reliability of PBPK models in general.

Adult↗

PubMed2000

Contractile and relaxing mechanisms in pulmonary resistance arteries of the preterm fetal lamb.

Isolated pulmonary resistance arteries from term fetal lambs have nitric oxide (NO)- and prostaglandin-mediated relaxing mechanisms which are activated when PO(2) is raised from fetal to neonatal levels. The same vessels contract under hypoxia, and the contraction has been ascribed to endothelin-1 (ET-1). We have now studied these vasoeffector mechanisms before term (0.7 and 0.65 gestation) with the objective of determining whether their activity correlates with the development of susceptibility to oxygen changes. Experiments were carried out at neonatal PO(2), when expectedly relaxing mechanisms are maximally expressed, or under hypoxia. At either fetal age, the NO synthesis inhibitor, N(G)-nitro-L-arginine methyl ester (100 microM), had no effect on basal tone, while indomethacin (2.8 microM) was a weak constrictor. Premature arteries did not contract when first exposed to hypoxia, but they responded marginally to a second exposure. The same arteries contracted strongly to a thromboxane A(2) analogue (ONO-11113, 0.1 microM) and ET-1 (10 nM), while their contraction to activating solution (5 mM Ca(2+) in K(+)-Krebs solution) was small and variable. At 0.7 gestation, bradykinin (0.1-100 nM), acetylcholine (0.01-10 microM), and sodium nitroprusside (0.1 nM to 10 microM) dose-dependently relaxed arteries precontracted with ONO-11113. Conversely, at 0.65 gestation the relaxation to bradykinin and acetylcholine was not dose-dependent and tended to be weaker. We conclude that preterm pulmonary arteries have viable effector mechanisms for contraction and relaxation. However, the capability for these mechanisms to be activated by PO(2) changes is markedly curtailed.

Acetylcholine↗

PubMed2002

Associations between MeCP2 mutations, X-chromosome inactivation, and phenotype.

Rett syndrome is a neurodevelopmental disorder of early postnatal brain growth in girls. Patients show a normal neonatal period with subsequent developmental regression and a loss of acquired skills (communication and motor skills), deceleration of head growth, and development of typical hand stereotypies. Recent studies have shown that mutations in the X-linked methyl CpG binding protein 2 gene (MeCP2) cause most typical cases of Rett syndrome. The MeCP2 gene encodes a protein that binds methylated cytosine residues of CpG dinucleotides and mediates, with histone deacetylases and transcriptional repressors, the transcription "silencing" of other genes. Girls with Rett syndrome exhibit mosaic expression for the MeCP2 defect at the cellular level, with most patients showing random X-inactivation and approximately equal numbers of cells expressing the normal MeCP2 gene and the mutated MeCP2 gene. In rare cases, females with a MeCP2 mutation escape phenotypic expression of the disorder because of nonrandom X-inactivation and the preferential inactivation of the mutated MeCP2 allele. Nonrandom patterns of X-inactivation may also contribute to the clinical variability often seen in girls with Rett syndrome. The spectrum of clinical phenotype caused by MeCP2 mutations is wide, including milder "preserved speech" variants, the severe congenital Rett variant, and a subset of X-linked recessive mental retardation in boys. Studies have shown that atypical and classical Rett syndrome can caused by the same MeCP2 mutations, indicating clinical phenotype is variable even among girls with the same MeCP2 mutation. The relationship between type of MeCP2 mutation, X-inactivation status, and clinical phenotype of Rett syndrome is complex and likely involves other environmental and polygenic modifiers.

Chromosomal Proteins, Non-Histone↗

PubMed2004

A rapid and simple method for determination of halothane, isoflurane and sevoflurane in blood using gas chromatography.

We have developed a technique to determine the concentration of volatile anesthetics (halothane, isoflurane and sevoflurane) in blood that is a modification of a method used for volatile anesthetics in Krebs solution. Methylene chloride was the internal standard and chloroform was used to extract the volatile anesthetic from blood. The congealed blood proteins were separated from the chloroform solvent (containing anesthetic) using a two-compartment vial that filtered out the proteinaceous material during centrifuging. Recovery averaged 102%. Linearity was excellent (r = 0.992-0.999) in the 50-600, 50-300 and 50-300 microg/mL range for halothane, isoflurane and sevoflurane, respectively. Intra-day and inter-day precisions were likewise excellent, with relative standard deviations <5.3 and <7.1%, respectively. Accuracy ranged from 0.8 to 9.5% of the estimated theoretical value. Extracted anesthetic in chloroform solvent was stable over 4-5 days, with <3% variability. The time from obtaining the blood sample to determination of the concentration from the chromatographic peak was 15 min or less.

Animals↗

PubMed2000

A comparative study of the structure of the rDNA intergenic spacer of Lens culinaris Medik., and other legume species.

As part of a project on lentil molecular genetics, the sequence of the 18S-25S ribosomal RNA gene intergenic spacer (IGS) of Lens culinaris Medik. was determined. DNA was cloned after polymerase chain reaction (PCR) amplification. The spacer of 2939 bp was composed of nonrepetitive sequences and four tandem arrays of repeated sequences, named A to D. C and D arrays were formed by the repetition of very short consensus sequences. Similarity was found between lentil and other legume species, in particular those of the Vicieae tribe. A transcription initiation site, putative sites of termination and processing, and promoter-enhancer sequences were detected by computer-aided searches. These sites resemble motifs conserved in the IGS sequences of other plant species. The conservation of motifs in the otherwise highly variable plant IGS sequences points to the relevance of these motifs as functional sequences.

Base Sequence↗

PubMed2001

Cardiac sympathetic overactivity and decreased baroreflex sensitivity in L-NAME hypertensive rats.

The present study evaluated the possible changes in the autonomic control of heart rate in the hypertensive model induced by the inhibition of nitric oxide synthase. Rats were treated with N(G)-nitro-L-arginine methyl ester (L-NAME group) in the drinking water during 7 days, whereas control groups were treated with tap water (control group) or with the N(G)-nitro-D-arginine methyl ester (D-NAME group), an inactive isomer of the L-NAME molecule. The L-NAME group developed hypertension and tachycardia. The sequential blockade of the autonomic influences with propranolol and methylatropine indicated that the intrinsic heart rate did not differ among groups and revealed a sympathetic overactivity in the control of heart rate in the L-NAME group. The spectral density power of heart rate, calculated using fast-Fourier transformation, indicated a reduced variability in the low-frequency band (0.20-0.60 Hz) for the L-NAME group. The baroreflex sensitivity was also attenuated in these animals when compared with the normotensive control or D-NAME group. Overall, these data indicate cardiac sympathetic overactivity associated with a decreased baroreflex sensitivity in L-NAME hypertensive rats.

Animals↗

PubMed1997

Variability of cerebral blood flow deficits in 99mTc-HMPAO SPECT in patients with Alzheimer's disease.

The purpose of this study was to analyse the frequency of the different pathological perfusion patterns in SPECT in a clinical, unselected population of patients with Alzheimer's disease. In 91 patients and 16 control subjects regional cerebral blood flow (rCBF) was measured with Single Photon Emission Computed Tomography (SPECT) using 99mTc-hexa-methyl-propyleneamine oxime (HMPAO). 95% confidence intervals obtained from the perfusion values of the control subjects were used to define normal perfusion ranges. The frequency of perfusion deficits in the left frontal, temporal, parietal and occipital lobes were 62.2%, 60.4%. 70.3% and 23.1%, respectively. In the right hemisphere the corresponding values were 60.4%, 58.2%, 63.7% and 9.9%. With the exception of the occipital lobes these frequencies were not significantly different. The analysis of the perfusion pattern of each patient revealed 35 different combinations of lobes with perfusion deficits. The temporo-parietal perfusion deficits were not more frequent than the temporofrontal perfusion deficits. These results suggest that in the clinical routine a high variety of heterogeneous rCBF patterns have to be expected.

Aged↗

PubMed2005

Bursting of prefrontal cortex neurons in awake rats is regulated by metabotropic glutamate 5 (mGlu5) receptors: rate-dependent influence and interaction with NMDA receptors.

Metabotropic glutamate 5 (mGlu5) receptors have been recently implicated in prefrontal cortex (PFC)-dependent executive functions because inhibition of mGlu5 receptors impairs working memory and worsens cognitive-impairing effects of NMDA receptor antagonists. To better understand the mechanisms by which mGlu5 receptors influence PFC function, we examined the effects of selective mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), given alone or in combination with the NMDA receptor antagonist MK801, on ensemble single unit activity in the medial PFC (mPFC) of behaving rats. MPEP decreased the spontaneous burst activity of the majority of mPFC neurons. This inhibition was selective for the most active cells because greater decreases were observed in neurons with higher baseline firing rates. MPEP augmented the effects of MK801 on burst activity, variability of spike firing and random spike activity. These findings demonstrate that in awake animals mGlu5 receptors regulate the function of PFC neurons by two related mechanisms: (i) rate-dependent excitatory influence on spontaneous burst activity; and (ii) potentiation of NMDA receptor mediated effects on firing rate and burst activity. These mechanisms support the idea that modulation of mGlu5 receptors may provide a pharmacological strategy for fine-tuning the temporal pattern of firing of PFC neurons.

Action Potentials↗

PubMed1982

Perspectives in molecular mutagenesis.

The models and paradigms that underlie a vigorously developing science may tend to stifle progress or may serve to sharpen the knife edge of paradox. Working out mutagenic mechanisms is a conceptually and technologically demanding task, and we are accumulating an increasingly uncomfortable number of experimental and theoretical inconsistencies. First, there continue to be widespread difficulties in specifying the chemical nature of mutagenic DNA alterations, both because of the multitude of DNA reaction products induced by many mutagens and because of the intrinsic rarity of most mutational responses. For instance, alkylation of the 0(6) position of guanine to generate adducts of modest dimensions is widely believed to form the basis for the mutagenic and carcinogenic actions of numerous chemicals. However, while this scheme is supported by in vitro evidence, it has failed to explain why bacteriophages can be thus alkylated in vitro by N-methyl-N'-nitro-N-nitrosoguanidine without the production of mutations, or why microbial eukaryotes alkylated by ethyl methanesulfonate or N-methyl-N'-nitro-N-nitrosoguanidine display no mutagenic response when their "error-prone repair systems" are mutationally inactivated. Second, a base pair is typically mutated at vastly different rates, and with different directional specificities, when it resides at different positions within a gene; whereas very little of this variability is explained by current theories that aim to describe the determinants of fidelity in DNA replication. (Some sizable portion of this variation now appears to depend not only upon neighboring base-pair influences but also upon much more subtle and distant effects). Third, experimental modifications of enzymatic fidelity by means of amino acid substitutions, and perhaps also cation replacements, lead to such a diversity of modified mutation rates as to seriously challenge the ability of any simple theory to organize the experimental observations into a coherent and predictive network.

Alkylation↗