Epileptogenesis: can the science of epigenetics give us answers?
Ontology highlight
ABSTRACT:
SUBMITTER: Lubin FD
PROVIDER: S-EPMC3367416 | biostudies-other | 2012 May
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Enhanced levels of Matrix Metalloproteinase-9 (MMP-9) have been implicated in the pathogenesis of epilepsy in humans and rodents. Lack of Mmp-9 impoverishes, whereas excess of Mmp-9 facilitates epileptogenesis. Epigenetic mechanisms driving the epileptogenesis-related upregulation of MMP-9 expression are virtually unknown. The aim of this study was to reveal these mechanisms. We analyzed hippocampi extracted from adult and pediatric patients with temporal lobe epilepsy as well as from partially and fully pentylenetetrazole kindled rats. We used a unique approach to the analysis of the kindling model results (inclusion in the analysis of rats being during kindling, and not only a group of fully kindled animals), which allowed us to separate the molecular effects exerted by the epileptogenesis from those related to epilepsy and epileptic activity. Consequently, it allowed for a disclosure of molecular mechanisms underlying causes, and not consequences, of epilepsy. Our data show that the epileptogenesis-evoked upregulation of Mmp-9 expression is regulated by removal from Mmp-9 gene proximal promoter of the two, interweaved potent silencing mechanisms-DNA methylation and Polycomb Repressive Complex 2 (PRC2)-related repression. Demethylation depends on a gradual dissociation of the DNA methyltransferases, Dnmt3a and Dnmt3b, and on progressive association of the DNA demethylation promoting protein Gadd45? to Mmp-9 proximal gene promoter in vivo. The PRC2-related mechanism relies on dissociation of the repressive transcription factor YY1 and the dissipation of the PRC2-evoked trimethylation on Lys27 of the histone H3 from the proximal Mmp-9 promoter chromatin in vivo. Moreover, we show that the DNA hydroxymethylation, a new epigenetic DNA modification, which is localized predominantly in the gene promoters and is particularly abundant in the brain, is not involved in a regulation of MMP-9 expression during the epileptogenesis in the rat hippocampus as well as in the hippocampi of pediatric and adult epileptic patients. Additionally, we have also found that despite of its transient nature, the histone modification H3S10ph is strongly and gradually accumulated during epileptogenesis in the cell nuclei and in the proximal Mmp-9 gene promoter in the hippocampus, which suggests that H3S10ph can be involved in DNA demethylation in mammals, and not only in Neurospora. The study identifies MMP-9 as the first protein coding gene which expression is regulated by DNA methylation in human epilepsy. We present a detailed epigenetic model of the epileptogenesis-evoked upregulation of MMP-9 expression in the hippocampus. To our knowledge, it is the most complex and most detailed mechanism of epigenetic regulation of gene expression ever revealed for a particular gene in epileptogenesis. Our results also suggest for the first time that dysregulation of DNA methylation found in epilepsy is a cause rather than a consequence of this condition.
| S-EPMC4978505 | biostudies-literature
Project description:Given the public interest in epigenetic science, this study aimed to better understand media representations of epigenetics in national newspaper coverage in various regions in North America, Europe, and Asia. Content analysis was used to study media messages about epigenetics, their policy focus, and the balance of the reporting. We identified several recurring themes in the news reports, including policy messages relating to individual and societal responsibilities. We also found shortcomings in the media's portrayal of epigenetic science, and sought to identify potential causes by considering the underlying scientific evidence that the media reported on. A case study analysis showed that the results of epigenetic studies were often overstated in academic research publications due to common experimental limitations. We suggest that defining standardized criteria with which to evaluate epigenetic studies could help to overcome some of the challenges inherent in translating complex epigenetic research findings for non-technical audiences, and present a Press Kit template that researchers can adapt and use to aid in the development of accurate and balanced press releases.
| S-EPMC7673471 | biostudies-literature
Project description:Our knowledge on microbial biogeography depends on the way we define and study diversity. In contrast to most microbes, some protist lineages have conspicuous structures that allow comparisons of diversity concepts and measures-those based on molecules and those based on morphology. We analyzed a group of shell-bearing planktonic ciliates, the tintinnids, in a coast-to-ocean gradient using high-throughput sequencing and microscopy. First, we compared molecular operational taxonomic units (OTUs) and morphospecies in terms of assemblage composition, distribution and relationships with the environment. OTUs revealed potentially novel and rare taxa, while morphospecies showed clearer correlations with environmental factors, and both approaches coincided in supporting a coastal versus oceanic pattern. Second, we explored which processes influence assembly across the environmental gradient examined. Assemblage fluctuations were associated with significant distance-decay and changes in morphospecies size and prey proxies, thus suggesting niche partitioning as a key structuring mechanism. Our conclusion is that molecules and morphologies generally agreed, but they provided complementary data, the first revealing hidden diversity, and the latter making better connections between distribution patterns and ecological processes. This highlights the importance of linking genotypes and phenotypes (using multidisciplinary analyses and/or reliable databases of barcoded species), to understand the diversity, biogeography and ecological roles of microbes.
| S-EPMC4918432 | biostudies-literature
Project description:ObjectivesWe aimed to (1) evaluate the extent to which doctors in New Zealand would be willing to answer honestly questions about their care of patients at the end of their lives and (2) identify the assurances that would encourage this. Results were compared with findings from a previous pilot study from the UK.DesignSurvey study involving a mailed questionnaire.SettingNew Zealand hospital and community-based medical care settings.ParticipantsThe questionnaire was mailed to a random sample of 800 doctors in New Zealand who were vocationally registered with the Medical Council of New Zealand in disciplines involving caring for patients at the end of their lives.Primary and secondary outcome measuresWillingness to provide honest answers about various aspects of end-of-life care; assurances that might increase willingness to provide honest answers to questions about end-of-life practices.ResultsCompleted questionnaires were returned by 436 doctors. The majority of respondents (59.9-91.5%) indicated willingness to provide honest answers to such questions. However, more than a third of doctors were unwilling to give honest answers to certain questions regarding euthanasia. These results are comparable with the UK data. Complete anonymity was the assurance most likely to encourage honest answering, with most of the respondents preferring the use of anonymous written replies. Respondents were less reassured by survey endorsements from regulatory bodies. Themes in free comments included the deterrent effect of medicolegal consequences, fear of censure from society, peers and the media and concerns about the motivations and potential uses of such research.ConclusionsMany New Zealand doctors were willing to give honest answers to questions about end-of-life practices, particularly if anonymity was guaranteed; others, however, expressed doubts or indicated that they would not be willing to provide honest answers to questions of this sort.
| S-EPMC3664351 | biostudies-literature
Project description:The societal importance of renewable carbon-based commodities and energy carriers has elicited a particular interest for high performance phototrophic microorganisms. Selection of optimal strains is often based on direct comparison under laboratory conditions of maximal growth rate or additional valued features such as lipid content. Instead of reporting growth rate in culture, estimation of photosynthetic efficiency (quantum yield of PSII) by pulse-amplitude modulated (PAM) fluorimetry is an often applied alternative method. Here we compared the quantum yield of PSII and the photonic yield on biomass for the green alga Chlorella sorokiniana 211-8K and the cyanobacterium Synechocystis sp. PCC 6803. Our data demonstrate that the PAM technique inherently underestimates the photosynthetic efficiency of cyanobacteria by rendering a high F0 and a low FM, specifically after the commonly practiced dark pre-incubation before a yield measurement. Yet when comparing the calculated biomass yield on light in continuous culture experiments, we obtained nearly equal values for both species. Using mutants of Synechocystis sp. PCC 6803, we analyzed the factors that compromise its PAM-based quantum yield measurements. We will discuss the role of dark respiratory activity, fluorescence emission from the phycobilisomes, and the Mehler-like reaction. Based on the above observations we recommend that PAM measurements in cyanobacteria are interpreted only qualitatively.
| S-EPMC4578884 | biostudies-literature
Project description:Computing is highly segregated and stratified by gender. While there is abundant scholarship investigating this problem, emerging evidence suggests that a hierarchy of value exists between the social and technical dimensions of Computer Science and Engineering (CSE) and this plays a role in the underrepresentation of women in the field. This ethnographic study of women's experiences in computing offers evidence of a systemic preference for the technical dimensions of computing over the social and a correlation between gender and social aspirations. Additionally, it suggests there is a gap between the exaltation of computing's social contributions and the realities of them. My participants expressed a yearning to contribute to the collective well-being of society using their computing skills. I trace moments of rupture in my participants' stories, moments when they felt these aspirations were in conflict with the cultural values in their organizations. I interpret these ruptures within a consideration of yearning, a need my participants had to contribute meaningfully to society that remained unfulfilled. The yearning to align one's altruistic values with one's careers aspirations in CSE illuminates an area for greater exploration on the path to realizing gender equity in computing. I argue that before a case can be made that careers in computing do indeed contribute to social and civil engagements, we must first address the meaning of the social within the values, ideologies and practices of CSE institutions and next, develop ways to measure and evaluate the field's contributions to society.
| S-EPMC5513966 | biostudies-literature
Project description:Gestational trophoblastic disease (GTD) is a group of conditions that originate from the abnormal hyperproliferation of trophoblastic cells, which derive from the trophectoderm, the outer layer of the blastocyst that would normally develop into the placenta during pregnancy. GTDs encompass hydatidiform mole (HM) (complete and partial), invasive mole, gestational choriocarcinoma, placental-site trophoblastic tumor, and epithelioid trophoblastic tumor. Of these, the most common is HM, and it is the only one that has been reported to recur in the same patients from independent pregnancies, which indicates the patients' genetic predisposition. In addition, HM is the only GTD that segregates in families according to Mendel's laws of heredity, which made it possible to use rare familial cases of recurrent HMs (RHMs) to identify two maternal-effect genes, NLRP7 and KHDC3L, responsible for this condition. Here, we recapitulate current knowledge about RHMs and conclude with the role and benefits of testing patients for mutations in the known genes.
| S-EPMC3920063 | biostudies-literature
Project description:The stereotype that children who are more able solve tasks quicker than their less capable peers exists both in and outside education. The F > C phenomenon and the distance-difficulty hypothesis offer alternative explanations of the time needed to complete a task; the former by the response correctness and the latter by the relative difference between the difficulty of the task and the ability of the examinee. To test these alternative explanations, we extracted IRT-based ability estimates and task difficulties from a sample of 514 children, 53% girls, M(age) = 10.3 years; who answered 29 Piagetian balance beam tasks. We used the answer correctness and task difficulty as predictors in multilevel regression models when controlling for children's ability levels. Our results challenge the 'faster equals smarter' stereotype. We show that ability levels predict the time needed to solve a task when the task is solved incorrectly, though only with moderately and highly difficult items. Moreover, children with higher ability levels take longer to answer items incorrectly, and tasks equal to children's ability levels take more time than very easy or difficult tasks. We conclude that the relationship between ability, task difficulty, and answer correctness is complex, and warn education professionals against basing their professional judgment on students' quickness.
| S-EPMC10143123 | biostudies-literature
Project description:Network medicine is a molecular-bioinformatic approach analyzing gene-gene interactions that can perturb the human interactome. This review focuses on epigenetic changes involved in several ocular diseases, such as DNA methylation, histone and nonhistone post-translational modifications, and noncoding RNA regulators. Although changes in aberrant DNA methylation play a major role in the pathogenesis of most ocular diseases, histone modifications are seldom investigated. Hypermethylation in TGM-2 and hypomethylation in MMP-2/CD24 promoter genes may play a crucial role in pterygium development; hypermethylation in regulatory regions of GSTP1 and OGG1 genes appear to be diagnostic biomarkers of cataract; hypomethylation of TGF-β1 promoter may trigger glaucoma onset; hypermethylation of the LOXL1 gene might be associated with pseudoexfoliation syndrome. A large panel of upregulated micro-RNAs (miRNAs), including hsa-hsa-miR-494, hsa-let-7e, hsa-miR-513-1, hsa-miR-513-2, hsa-miR-518c, hsa-miR-129-1, hsa-miR-129-2, hsa-miR-198, hsa-miR-492, hsa-miR-498, hsa-miR-320, hsa-miR-503, and hsa-miR-373, ∗ may have a putative role in the development of retinoblastoma. Hypermethylation of H3K4 and hypomethylation of H3K27 at the TGFBIp locus are putative pathogenic mechanisms involved in corneal dystrophies. Determining how, where, and when specific epigenetic changes trigger ocular diseases may provide useful clinical biomarkers for their prevention, diagnosis, and management, as well as innovative drug targets. PF-04523655, a 19-nucleotide methylated double-stranded siRNA targeting the RTP80 gene, showed a dose-related improvement in best-corrected visual acuity (BCVA) in patients affected by diabetic macular edema. The observed results support a clinical network-based research program aimed to clarify the role of epigenetic regulators in the development of ocular diseases and personalized therapy.
| S-EPMC6959156 | biostudies-literature
Project description:experimental group and control group in rat post-status epilepticus model. Keywords: parallel sample
2003-10-31 | GSE785 | GEO