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Results for “variable methylation”

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PubMed1994

Pervasive CpG suppression in animal mitochondrial genomes.

All available complete mitochondrial genomes (21 species) are evaluated for dinucleotide over- and under-representation. The CpG dinucleotide is pervasively under-represented in all animal mitochondria, but it is of variable relative abundance in fungal, protist, and plant mitochondrial genomes. Interpretations and hypotheses are considered relative to mitochondrial genome organization, methylation, structural specificities, directed mutation, and evolutionary events. In particular, our results support Mycoplasma capricolum or a close relative as the most likely bacterial ancestor of the mitochondria.

Base Composition↗

PubMed1975

Control of ovine lupinosis: experiments on the use of fungicides.

Experiments were conducted in 4 successive years to assess whether certain fungicides when applied to lupins would control the disease, ovine lupinosis. Results were variable, ranging from failure of fungicidal sprays to prevent the disease in 1969/70 to partial success in 1970/71. Fumigation with methyl bromide was very effective. It is concluded that none of the fungicides tried could be considered as a practical means of controlling the disease.

Animals↗

PubMed2026

Establishing a Multicenter Personalized Medicine Program in Childhood, Adolescent, and Young Adult Cancer in Spain: The SEHOP-PENCIL Project.

Pediatric cancer care in Spain lacked a national personalized medicine program. The SEHOP-PENCIL initiative, established by the SEHOP, was designed to address this gap. A national survey identified the genomic sequencing needs of hospitals treating pediatric patients with cancer. Results showed improved access to targeted next-generation sequencing panels but revealed persistent variability in implementation, limited availability of advanced sequencing (whole-exome sequencing, whole-genome sequencing, RNA sequencing, and DNA methylation profiling), and gaps in cancer predisposition clinics and molecular tumor boards (MTBs). SEHOP-PENCIL is organized as a network of 10 specialized genomic centers serving 45 hospitals through a centralized inclusion system. The program standardizes patient eligibility, genomic workflows, and result interpretation, supported by a national MTB. This framework enables informed clinical decision making, ensures access to molecular diagnosis and innovative therapies, and supports systematic data collection to advance pediatric cancer research and personalized care. SEHOP-PENCIL represents a pioneering national model for integrating precision oncology into pediatric cancer care in Spain. By fostering collaboration, standardizing genomic practices, and promoting equitable access, it aims to reduce disparities and improve outcomes, offering a scalable example for other decentralized health care systems.

Humans↗

PubMedDate not supplied

[The biological monitoring of occupational exposures to solvents by using their urinary concentrations].

For many years biological monitoring of occupational exposure to solvents is achieved via their specific urinary metabolites. In the last 10 years many publications have shown that the urinary concentrations of unchanged solvents are well correlated with environmental exposure and could therefore be used for biological monitoring. For acetone, methanol, methyl ethyl ketone and methyl iso butyl ketone, the American Conference of Governmental Industrial Hygienists and the Deutsche Forschungsgemeinschaft have proposed urinary concentrations of substance itself as biological exposure indices. A critical revision of the literature on this matter reveals discrepancies between the results obtained by different authors. The correlations between environmental data and respective solvents give excellent indices of correlation. However, the differences observed when comparing the regression lines obtained from different research groups are very wide. For example, for an exposure to toluene corresponding to 50 ppm, some authors found urinary concentrations equal to 35 micrograms/l, others found urinary concentration higher than 100 micrograms/l. Similarly for benzene, styrene and methyl ethyl ketone the differences were also marked. We have not identified an explanation for such different results. Biological data variability could help to explain part of these disagreements. It should also be remembered that for benzene, the analytical methodology performed in different conditions can give rise to very different results. The mechanisms of excretion of organic solvents in urine are discussed considering biological variability and analytical method problems. The current hypotheses do not allow a satisfactory interpretation of the literature results. In conclusion further experience is needed that will more clearly show which results better express the relationship between occupational exposure to organic solvents and their specific urinary concentrations.

Body Burden↗

PubMed1991

Synthesis and anti-inflammatory activity of 5-(1,4-dihydropyridyl)-tetrazol-2-acetic acids, esters and amides.

Thirteen 5-[3-(1,4-dihydropyridyl)]-2H-tetrazol-2-acetic acids (18-30), seventeen esters (4-17, 32, 35, 41) and eight amides (31, 32-34, 36-40) were synthesized in order to investigate the effect of alpha-substituents (R1 = H, Me) and 1,4-dihydropyridyl substituents (R2 = aryl, alkyl; R3 = phenoxy, methoxy or amino) on anti-inflammatory activity. The effects of the R1, R2 or R3-substituents were variable but highly interdependent. The relative order of anti-inflammatory potency was generally acid greater than amide and ester. Methyl 2-methyl-2-(5-[3-(4-phenyl-1-carbamoyl-1,4-dihydropyridyl)]-2H- tetrazol-2-yl) acetate (35) was the most effective anti-inflammatory agent in the group, reducing inflammation 96% at 5 hr after a 50 mg/kg po dose, relative to ibuprofen's 52% inhibition at 5 hr after a 100 mg/kg po dose.

Acetates↗

PubMed1976

[Hemodynamic effects of high-dosage corticoids. Their justification in the treatment of shock].

In 61 patients in whom high doses of corticoids had been administered owing to various indications, the hemodynamic modifications caused by this injection were studied. The corticoids administered were : hydrocortisone hemisucccinate (150 mg/kg), methyl prednisolone sulfate (30 mg/kg), prednisone sodium m sulfobenzoate (50 mg/kg), prednisolone sodium m sulfobenzoate (35 mg/kg) and dexamethasone phosphate (2 mg and 6 mg/kg). The results study the modifications caused by each drug on heart rate, arterial blood pressure, cardiac output, systolic stroke volume and peripheral vascular resistance. The expression of the results is given as a percentage of the variation with statistical study. Methyl-prednisolone sulfobenzoate only leads to slightly marked hemodynamic effects : the four other compounds studied have definite hemodynamic effects, of variable intensity and duration. The most important variations are noted with dexametasone phosphate. From these results, the indications and results of the use of corticoids in states of shock are discussed.

Adrenal Cortex Hormones↗

PubMed2025

Genetic and epigenetic changes to the glucocorticoid receptor gene (NR3C1) and cognition in major depressive disorder.

INTRODUCTION: Many studies have found that hypothalamic-pituitary-adrenal (HPA) axis abnormalities are related to the pathophysiology of major depressive disorder (MDD) and cognitive functioning. Our aim was to assess the influence of genetic polymorphisms and methylation levels in three different promoter regions throughout the glucocorticoid receptor (GR) gene NR3C1 on cognitive performance in MDD. Plausible interactions with childhood adversity and mediation relationships between genetic and epigenetic variables were explored. MATERIALS AND METHODS: The sample included a total of 64 MDD patients and 82 healthy controls. Child maltreatment and neurocognitive performance were assessed in all participants. HPA negative feedback was analyzed using the dexamethasone suppression test after the administration of 0.25mg of dexamethasone. A total of 23 single-nucleotide polymorphisms were genotyped, and methylation levels at several CpGs in exons 1D, 1F and 1H of the GR gene were measured. RESULTS: Results show that, beyond the influence of other covariables, NR3C1 single-nucleotide polymorphisms and methylation levels predicted performance in executive functioning and working memory tasks. No significant interactions or mediation relationships were detected. CONCLUSIONS: Results suggest that genetic variations and epigenetic regulation of the GR gene are relevant factors influencing cognitive performance in MDD and could emerge as significant biomarkers and therapeutic targets in mood disorders and other stress-related disorders.

Humans↗

PubMed2003

Allele-specific methylation at the promoter-associated CpG island of mouse Copg2.

We previously reported that the mouse Copg2 (Coatomer Protein Subunit Gamma 2) gene was imprinted in the intraspecific F(1) hybrid mice between C57BL/6 and M. m. molossinus. In this study, methylation status at the promoter-associated CpG island and allele-specific expression pattern of Copg2 were investigated in the interspecific F(1) hybrid (C57BL/6 x M. spretus). We found that Copg2 was biallelically expressed in the interspecific F(1) hybrid, despite the presence of a differentially methylated region (DMR) in the CpG island. Therefore, paternal-specific methylation at the CpG island of Copg2 is not accompanied by allele-specific expression of Copg2 in the F(1) hybrid (C57BL/6 x M. spretus). The results suggest that the imprinted pattern of Copg2 expression is subject to variable epigenetic control systems of different mouse species. In addition, we identified a novel antisense transcript, Copg2AS2, at the Copg2 promoter region. The antisense transcript was expressed monoallelically, indicating that the differential expression of the antisense transcript is correlated with the differential methylation at the CpG island of Copg2.

Alleles↗

PubMed1996

Contribution of the renin-angiotensin system to short-term blood pressure variability during blockade of nitric oxide synthesis in the rat.

1. The aim of this study was to investigate, by use of spectral analysis, (1) the blood pressure (BP) variability changes in the conscious rat during blockade of nitric oxide (NO) synthesis by the L-arginine analogue NG-nitro-L-arginine methyl ester (L-NAME); (2) the involvement of the renin-angiotensin system in these modifications, by use of the angiotensin II AT1-receptor antagonist losartan. 2. Blockade of NO synthesis was achieved by infusion for 1 h of a low-dose (10 micrograms kg-1 min-1, i.v., n = 10) and high-dose (100 micrograms kg-1 min-1, i.v., n = 10) of L-NAME. The same treatment was applied in two further groups (2 x n = 10) after a bolus dose of losartan (10 mg kg-1, i.v.). 3. Thirty minutes after the start of the infusion of low-dose L-NAME, systolic BP (SBP) increased (+10 +/- 3 mmHg, P < 0.01), with the effect being more pronounced 5 min after the end of L-NAME administration (+20 +/- 4 mmHg, P < 0.001). With high-dose L-NAME, SBP increased immediately (5 min: +8 +/- 2 mmHg, P < 0.05) and reached a maximum after 40 min (+53 +/- 4 mmHg, P < 0.001); a bradycardia was observed (60 min: -44 +/- 13 beats min-1, P < 0.01). 4. Low-dose L-NAME increased the low-frequency component (LF: 0.02-0.2 Hz) of SBP variability (50 min: 6.7 +/- 1.7 mmHg2 vs 3.4 +/- 0.5 mmHg2, P < 0.05), whereas the high dose of L-NAME not only increased the LF component (40 min: 11.7 +/- 2 mmHg2 vs 2.7 +/- 0.5 mmHg2, P < 0.001) but also decreased the mind frequency (MF: 0.2-0.6 Hz) component (60 min: 1.14 +/- 0.3 mmHg2 vs 1.7 +/- 0.1 mmHg2, P < 0.05) of SBP. 5. Losartan did not modify BP levels but had a tachycardic effect (+45 beats min-1). Moreover, losartan increased MF oscillations of SBP (4.26 +/- 0.49 mmHg2 vs 2.43 +/- 0.25 mmHg2, P < 0.001), prevented the BP rise provoked by the low-dose of L-NAME and delayed the BP rise provoked by the high-dose of L-NAME. Losartan also prevented the amplification of the LF oscillations of SBP induced by L-NAME; the decrease of the MF oscillations of SBP induced by L-NAME was reinforced after losartan. 6. We conclude that the renin-angiotensin system is involved in the increase in variability of SBP in the LF range which resulted from the withdrawal of the vasodilating influence of NO. We propose that NO may counterbalance LF oscillations provoked by the activity of the renin-angiotensin system.

Animals↗

PubMed2005

Variable cytocompatibility of six cell lines with photoinitiators used for polymerizing hydrogels and cell encapsulation.

The development of biocompatible photopolymerizing polymers for biomedical and tissue engineering applications has the potential to reduce the invasiveness and cost of biomaterial implants designed to repair or augment tissues. However, more information is needed about the cellular toxicity of the compounds and initiators used in these systems. The current study evaluates the cellular toxicity of three ultraviolet sensitive photoinitiators on six different cell populations that are used for engineering numerous tissues. The photoinitiator 2-hydroxy-1-[4-(hydroxyethoxy)phenyl]-2-methyl-1-propanone (Irgacure 2959) caused minimal toxicity (cell death) over a broad range of mammalian cell types and species. It was also demonstrated that different cell types have variable responses to identical concentrations of the same photoinitiator. While inherent differences in the cell lines may contribute to the variable cytotoxicity, a correlation between cellular proliferation rate (population doubling time) and increased cytotoxicity of the photoinitiator was observed. Cell lines that divided more quickly were more sensitive to photoinitiator-induced cell death. In summary, the photoinitiator Irgacure 2959 is well tolerated by many cell types over a range of mammalian species. Cell photoencapsulation strategies may be optimized to improve cell survival by manipulating proliferation rate.

Biocompatible Materials↗

PubMed2005

Extended analyses support the association of a functional (GT)n polymorphism in the GRIN2A promoter with Japanese schizophrenia.

Dysfunction of the N-methyl-D-aspartate (NMDA) type glutamate receptor has been proposed as a mechanism in the etiology of schizophrenia. Recently, we identified a variable (GT)n repeat in the promoter region of the NMDA NR2A subunit gene (GRIN2A), and showed its association with schizophrenia in a case-control study, together with a correlation between the length of the repeat and severity of chronic outcome. In this study, we extended our analyses, by increasing the number of case-control samples to a total of 672 schizophrenics and 686 controls, and excluded potential sample stratification effects. We confirmed the significant allelic association between the repeat polymorphism and disease (P = 0.011), and as in the previous study, we observed an over-representation of longer alleles in schizophrenia. These results suggest a probable genetic effect for the GRIN2A promoter (GT)n variation on the predisposition to schizophrenia in Japanese cohorts.

Adult↗

PubMedDate not supplied

Characterizing "blue blobs". Immunohistochemical staining and ultrastructural study.

OBJECTIVE: To investigate the nature and origin of "blue blobs" (Bbs) in atrophic Pap smears in postmenopausal women and to study their clinical significance. STUDY DESIGN: A retrospective study of 412 atrophic Pap smears from postmenopausal women was done to detect the presence of Bbs. The smears from 24 cases showing Bbs were further studied to evaluate the nature of the Bbs with special stains, immunohistochemistry and electron microscopy. RESULTS: Bbs showed a heterogeneous morphology, with variable numbers and staining intensity. The diameter of Bbs was approximately equivalent to that of a parabasal/intermediate squamous cell. Special stains showed Bbs to be positive for periodic acid-Schiff and methyl green pyronin and negative for mucicarmine and calcium. Immunohistochemistry revealed Bbs to be positive for cytokeratin, epithelial membrane antigen and carcinoembryonic antigen and negative for vimentin and muscle-specific actin. Some Bbs had residual ghost nuclear shadows. Electron microscopy revealed cellular skeletons with residual tonofilaments enmeshed within a loose cytoskeleton matrix and nuclei with variable degrees of degeneration. CONCLUSION: Special stains, immunohistochemistry and electron microscopy indicated that Bbs represent parabasal/intermediate squamous cells exhibiting various degree of degeneration. In general, Bbs appear to be of no clinical significance except as a source of potential diagnostic error.

Aged↗

PubMed2000

Technical advance: the DNA-binding activity of gal4 is inhibited by methylation of the gal4 binding site in plant chromatin.

Derivatives of the Saccharomyces cerevisiae transcription factor Gal4 which act as effective transcription activators in yeast, Drosophila, mammalian cells and plant protoplasts are shown to direct expression from a GUS reporter construct when expressed in transgenic tobacco. However, in comparison to 35S-GUS controls, Gal4-mediated expression of the reporter gene was relatively weak and extremely variable. GUS expression was lost as plants matured and it was almost undetectable in most of their progeny. Gal4-mediated gene expression could be restored by treating tissues with 5-aza-cytidine, implicating cytosine methylation in the loss of Gal4-mediated expression. Restoration of reporter expression was not accompanied by an increase in steady-state levels of the activator transcript. We propose that the DNA-binding activity of Gal4 is sensitive to methylation of its binding site in plant chromatin. The Gal4-DNA co-crystal predicts that 5-methylcytosine at either of the outer two positions of the binding site will effectively prevent Gal4 binding. We show that these positions become extensively methylated in transgenic plants and that methylation of Gal4-binding sites interferes with Gal4 binding in vitro. These observations suggest that the Gal4 DNA-binding domain is intrinsically sensitive to cytosine methylation and that, despite the success of Gal4-based expression systems in yeast and Drosophila, Gal4 is not ideal for use in plant gene expression technology.

Azacitidine↗

PubMed1996

FISH detection of chromosome 15 deletions in Prader-Willi and Angelman syndromes.

We have evaluated fluorescence in situ hybridization (FISH) analysis for the clinical laboratory detection of the 15q11-q13 deletion seen in Prader-Willi syndrome (PWS) and Angelman syndrome (AS) using probes for loci D15S11, SNRPN, D15S10, and GABRB3. In a series of 118 samples from patients referred for PWS or AS, 29 had deletions by FISH analysis. These included two brothers with a paternally transmitted deletion detectable with the probe for SNRPN only. G-banding analysis was less sensitive for deletion detection but useful in demonstrating other cytogenetic alterations in four cases. Methylation and CA-repeat analyses of 15q11-q13 were used to validate the FISH results. Clinical findings of patients with deletions were variable, ranging from newborns with hypotonia as the only presenting feature to children who were classically affected. We conclude that FISH analysis is a rapid and reliable method for detection of deletions within 15q11-q13 and whenever a deletion is found, FISH analysis of parental chromosomes should also be considered.

Angelman Syndrome↗

PubMed1998

Genetic approaches to the neurobiology of electroconvulsive therapy.

Although electroconvulsive therapy effectively treats severe psychiatric disorders, its neurobiologic mechanisms are not fully understood. Also unclear is the basis for variability in seizure threshold and duration among patients. We used multiple strains of rats and mice to test for genetic variation in the properties of seizures induced by electroconvulsive shock (ECS). We specifically measured seizure duration, sensitivity to proconvulsant actions of caffeine, and relative refractoriness to postictal induction of further seizures, all of which showed significant interstrain variability. In addition, tonic-clonic seizure durations correlated with rates of immediate mortality, suggesting variations in underlying levels of cellular excitability across strains. By using quantitative autoradiography to relate these findings to neurobiologic mechanisms, we found significant correlations between hippocampal A1-receptor binding, cortical and striatal N-methyl-D-aspartate (NMDA)-receptor binding, and the modification of seizure duration by caffeine. These studies suggest that heritable factors modulate the neurobiologic determinants of electrically induced seizures. Furthermore, they suggest that genetic factors may contribute to clinically observed variability in seizure thresholds. Finally, the data provide a basis for future molecular genetic approaches to link ECS-induced changes in seizure properties to relevant transmitter systems.

Animals↗

PubMed2006

Methylation of two Homo sapiens-specific X-Y homologous genes in Klinefelter's syndrome (XXY).

An increased incidence of psychiatric and structural brain abnormalities in individuals with Klinefelter syndrome (KS, 47 XXY) could be due to the presence of extra copies of X-Y homologous genes that escape X inactivation. Of particular interest are the two brain-expressed genes Protocadherin11XY (PCDH11XY) and the Synaptobrevin-like gene (SYBL1) which have been duplicated from the X chromosome to the Y chromosome to give X-Y homologous gene pairs that are specific to modern humans. We examined the DNA of KS individuals reported recently by DeLisi et al. 2005 and determined the parental origin of the X alleles, the degree of skewed X inactivation and investigated the CpG island methylation status of PCDH11XY and SYBL1 by bisulphite sequencing and quantification of methylated HpaII sites. We used a novel method for quantification of unmethylated CpGs with the restriction enzyme McrBC which cuts methylated but not unmethylated CpGs. The results showed that KS individuals have two methylated and one unmethylated SYBL1 allele whereas PCDH11XY is unmethylated and escapes X inactivation on the extra X chromosome. Overexpression of PCDH11XY in KS is probable and variable escape from inactivation of this Homo sapiens-specific gene could account for some abnormalities in KS. The origin of the parental alleles or their preferential X inactivation was not associated with psychotic symptoms.

Alleles↗

PubMed1977

Studies on some characteristics of hydrogen production by cell-free extracts of rumen anaerobic bacteria.

Hydrogen production was studied in the following rumen anaerobes: Bacteroides clostridiiformis, Butyrivibrio fibrisolvens, Enbacterium limosum, Fusobacterium necrophorum, Megasphaera elsdenii, Ruminococcus albus, and Ruminococcus flavefaciens. Clostridium pasteurianum and Escherichia coli were included for comparative purposes. Hydrogen production from dithionite, dithionite-reduced methyl viologen, pyruvate, and formate was determined. All species tested produced hydrogen from dithionite-reduce methyl viologen, but only C. pasteurianum, B. clostridiiformis, E. limosum, and M. elsdenii produced hydrogen from dithionite. All species except E. coli produced hydrogen from pyruvate, but activity was low or absent in extracts of E. limosum, F. necrophorum, R. albus, and R. flavefaciens unless methyl viologen was added. Hydrogen was produced from formate only by E. coli, B. clostridiiformis, E. limosum, F. necrophorum, and R. flavefaciens. Extracts were subjected to ultracentrifugation in an effort to determine the solubility of hydrogenase. The hydrogenase of all species except E. coli appeared to be soluble, although variable amounts of hydrogenase activity were detected in the pellet. Treatment of extracts of the rumen microbial species with DEAE-cellulose resulted in loss ofhydrogen production from pyruvate. Activity was restored by the addition of methyl viologen. It is concluded that hydrogen production in these rumen microorganisms is similar to that in the saccharolytic clostridia.

Anaerobiosis↗

PubMed2003

Age-related epigenetic changes and the immune system.

The role of DNA methylation in immune function is discussed extensively in other papers in this issue. Many of these discussions assume that DNA methylation, a major mediator of epigenetic information, is fairly immutable and uniform in adult cells and tissues. There is, however, growing evidence that DNA methylation changes subtly with age. Normal aging cells and tissues show a progressive loss of 5-methylcytosine content, primarily within DNA repeated sequences, but also in potential gene regulatory areas. In parallel, selected genes show progressive age-related increases in promoter methylation, which, once a critical methylation density is reached, have the potential to permanently silence gene expression. These changes are highly mosaic within a given tissue and introduce a high degree of epigenetic variability in aging cells. Such epigenetic phenomena could impact immune response through masking/unmasking potential tissue antigens as well as by modulating the differentiation and response of immune effector cells. The contribution of epigenetic changes to the altered immune function observed in aging humans deserves careful investigation.

Aging↗