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Mitochondrial dna methylation and human diseases
Full text linkEpigenetic modifications of the nuclear genome, including DNA methylation, histone modifications and non-coding RNA post-transcriptional regulation, are increasingly being involved in the pathogenesis of several human diseases. Recent evidence suggests that also epigenetic modifications of the mitochondrial genome could contribute to the etiology of human diseases. In particular, altered methylation and hydroxymethylation levels of mitochondrial DNA (mtDNA) have been found in animal models and in human tissues from patients affected by cancer, obesity, diabetes and cardiovascular and neurodegenerative diseases. Moreover, environmental factors, as well as nuclear DNA genetic variants, have been found to impair mtDNA methylation patterns. Some authors failed to find DNA methylation marks in the mitochondrial genome, suggesting that it is unlikely that this epigenetic modification plays any role in the control of the mitochondrial function. On the other hand, several other studies successfully identified the presence of mtDNA methylation, particularly in the mitochondrial displacement loop (D-loop) region, relating it to changes in both mtDNA gene transcription and mitochondrial replication. Overall, investigations performed until now suggest that methylation and hydroxymethylation marks are present in the mtDNA genome, albeit at lower levels compared to those detectable in nuclear DNA, potentially contributing to the mitochondria impairment underlying several human diseases
Mitoepigenetics and Neurodegenerative Diseases
Full text linkMitochondrial impairment and increased oxidative stress are common features in neurodegenerative disorders, leading researchers to speculate that epigenetic changes in the mitochondrial DNA (mitoepigenetics) could contribute to neurodegeneration. The few studies performed so far to address this issue revealed impaired methylation levels of the mitochondrial regulatory region (D-loop region) in both animal models, postmortem brain regions, or circulating blood cells of patients with Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Those studies also revealed that mtDNA D-loop methylation levels are subjected to a dynamic regulation within the progression of the neurodegenerative process, could be affected by certain neurodegenerative disease-causative mutations, and are inversely correlated with the mtDNA copy number. The methylation levels of other mtDNA regions than the D-loop have been scarcely investigated in human specimens from patients with neurodegenerative disorders or in animal models of the disease, and evidence of impaired methylation levels is often limited to a single study, making it difficult to clarify their correlation with mitochondrial dynamics and gene expression levels in these disorders. Overall, the preliminary results of the studies performed so far are encouraging making mitoepigenetics a timely and attractive field of investigation, but additional research is warranted to clarify the connections among epigenetic changes occurring in the mitochondrial genome, mitochondrial DNA dynamics and gene expression, and the neurodegenerative process
Epigenetic effects of nano-sized materials.
No full textThe term epigenetics includes several phenomena such as DNA methylation, histone tail modifications, and microRNA mediated mechanisms, which are able to mold the chromatin structure and/or gene expression levels, without altering the primary DNA sequence. Environmental agents can exert epigenetic properties and there is increasing evidence of epigenetic deregulation of gene expression in several human diseases, including cancer, cardiovascular diseases, autism spectrum disorders, autoimmune diseases, and neurodegeneration, among others. Given the widespread use and dispersion in the environment of nano-sized materials, this article summarizes the studies performed so far to evaluate their potential epigenetic properties. Those studies highlight the ability of certain nano-sized compounds to induce an impaired expression of genes involved in DNA methylation reactions leading to global DNA methylation changes, as well as changes of gene specific methylation of tumor suppressor genes, inflammatory genes, and DNA repair genes, all potentially involved in cancer development. Moreover, some nano-sized compounds are able to induce changes in the acetylation and methylation of histone tails, as well as microRNA deregulated expression. We also provided a detailed description of currently available methodologies to evaluate epigenetic modifications. Standard protocols are currently available to evaluate cytotoxic and genotoxic effects of nano-sized materials. By contrast, there are at present no available standard protocols to evaluate the epigenetic potential of any given compound. The currently available methodologies offer different, but often complementary information to characterize potential epigenetic changes induced by exposure to nano-sized compounds. Given the widespread use and dispersion in the environment of nano-sized materials, at present and foreseeable in the near future, and in light of the indication of potential epigenetic properties here reviewed, more attention should be paid to unravel the consequences of such effects in future studies
Plasma homocysteine and polymorphisms of genes involved in folate metabolism correlate with DNMT1 gene methylation levels
Full text linkDNA methyltransferase 1 (DNMT1) is responsible for the maintenance of DNA methylation patterns during cell division. Several human diseases are characterized by impaired DNMT1 gene methylation, but less is known about the factors that regulate DNMT1 promoter methylation levels. Dietary folates and related B-vitamins are essential micronutrients for DNA methylation processes, and we performed the present study to investigate the contribution of circulating folate, vitamin B12, homocysteine, and common polymorphisms in folate pathway genes to the DNMT1 gene methylation levels. We investigated DNMT1 gene methylation levels in peripheral blood DNA samples from 215 healthy individuals. All the DNA samples were genotyped for MTHFR 677C > T (rs1801133) and 1298A > C (rs1801131), MTRR 66A > G (rs1801394), MTR 2756A > G (rs1805087), SLC19A1 (RFC1) 80G > A (rs1051266), TYMS 28-bp tandem repeats (rs34743033) and 1494 6-bp insertion/deletion (indel) (rs34489327), DNMT3A-448A > G (rs1550117), and DNMT3B-149C > T (rs2424913) polymorphisms. Circulating homocysteine, folate, and vitamin B12 levels were available from 158 of the recruited individuals. We observed an inverse correlation between plasma homocysteine and DNMT1 methylation levels. Furthermore, both MTR rs1805087 and TYMS rs34743033 polymorphisms showed a statistically significant effect on DNMT1 methylation levels. The present study revealed several correlations between the folate metabolic pathway and DNMT1 promoter methylation that could be of relevance for those disorders characterized by altered DNA methylation
Polymorphisms of genes required for methionine synthesis and DNA methylation influence mitochondrial DNA methylation
No full textAim: Impaired methylation of the mitochondrial DNA and particularly in the regulatory displacement loop (D-loop) region, is increasingly observed in patients with neurodegenerative disorders. The present study aims to investigate if common polymorphisms of genes required for one-carbon metabolism (MTHFR, MTRR, MTR and RFC-1) and DNA methylation reactions (DNMT1, DNMT3A and DNMT3B) influence D-loop methylation levels. Materials & methods: D-loop methylation data were available from 133 late-onset Alzheimer's disease patients and 130 matched controls. Genotyping was performed with PCR-RFLP or high resolution melting techniques. Results: Both MTRR 66A > G and DNMT3A -448A > G polymorphisms were significantly associated with D-loop methylation levels. Conclusion: This exploratory study suggests that MTRR and DNMT3A polymorphisms influence mitochondrial DNA methylation; further research is required to better address this issue
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Auraoxetanes as Plausible Intermediates in the Oxidation of Alkenes by Oxygen- Transfer Reaction from Gold(III) Oxo Complexes.
No full textAlkene oxidation by oxygen atom transfer reaction from late transition metal oxo complexes is, at present, an objective of particular interest. Metallaoxetanes, proposed as possible intermediates, have been recently isolated in the case of platinum(II).1 Intermediacy of metallaoxetanes in metal catalyzed alkene epoxidations has been proven in the case of silver as well.2
A series of gold(III) oxo complexes, [Au2(N,N)2(μ-O)2][PF6]2, supported by bidentate 6-substituted-2,2’- bipyridines, had been synthesized several years ago by some of us.3 Preliminary studies, indicating the feasibility of oxygen atom transfer reaction, were followed by extensive investigations on the alkene oxidation. The reaction with styrene, chosen as a model, was thoroughly studied and a gold(I) olefin complex [Au(N,N)(η2-CH2=CHPh][PF6] structurally characterised.4 Styrene oxygenated derivatives, contemporaneously formed, were identified as well. Analogous results have been successively obtained with other terminal olefins, while no reaction takes place with internal olefins. Following the hypothesis that gold(I) alkene complexes and alkene oxidation products could have been originated by a common precursor, and that the precursor was likely to be an auraoxacyclobutane, we thought to study the reaction with strained cyclic olefins, such as 2-norbornylene, nb, and 2,5-norbornadiene, nbd. These olefins, being rather reactive but lacking of active β-hydrogens, were good candidates for stabilizing a possible metallaoxetane intermediate. The reaction with both olefins proceeds slowly to give the gold(I) alkene complexes [Au2(N,N)2(μ-η4-nbd][PF6]2 and [Au(N,N)(η2-nb][PF6]2, respectively, as the main products. A second product of the reaction with nb, which depending on the substituent in 6 of the bipyridine and on the preparative conditions forms in appreciable amount, resulted to be an unprecedented auraoxetane [Au(bipyMe)(κ2-O,C-2- oxynorbornyl)][PF6].5 Plausible reaction pathways for the formation of the gold complexes and the oxygenated organic derivatives will be discussed.
References
[1] E. Szuromi, H. Shan, P.R. Sharp, J. Am. Chem. Soc. 2003, 125, 10522-10523;
[2] S. Linic, H. Piao, K. Adib, M.A. Barteau, Angew. Chem. Int. Ed. 2004, 43, 2918-2921.
[3] M.A. Cinellu, G. Minghetti, M.V. Pinna, S. Stoccoro, A. Zucca, M. Manassero, M. Sansoni, J. Chem. Soc., Dalton Trans. 1998,
1735-1741.
[4] M.A. Cinellu, G. Minghetti, S. Stoccoro, A. Zucca and M. Manassero, Chem. Commun., 2004, 1618-1619 [5] M.A. Cinellu, G. Minghetti, F. Cocco, S. Stoccoro, A. Zucca, M. Manassero, submitted
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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