DNA methylation is a heritable epigenetic modification involved in gene silencing, imprinting, and the suppression of retrotransposons. Global DNA demethylation occurs in the early embryo and the ...germ line, and may be mediated by Tet (ten eleven translocation) enzymes, which convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Tet enzymes have been studied extensively in mouse embryonic stem (ES) cells, which are generally cultured in the absence of vitamin C, a potential cofactor for Fe(II) 2-oxoglutarate dioxygenase enzymes such as Tet enzymes. Here we report that addition of vitamin C to mouse ES cells promotes Tet activity, leading to a rapid and global increase in 5hmC. This is followed by DNA demethylation of many gene promoters and upregulation of demethylated germline genes. Tet1 binding is enriched near the transcription start site of genes affected by vitamin C treatment. Importantly, vitamin C, but not other antioxidants, enhances the activity of recombinant Tet1 in a biochemical assay, and the vitamin-C-induced changes in 5hmC and 5mC are entirely suppressed in Tet1 and Tet2 double knockout ES cells. Vitamin C has a stronger effect on regions that gain methylation in cultured ES cells compared to blastocysts, and in vivo are methylated only after implantation. In contrast, imprinted regions and intracisternal A particle retroelements, which are resistant to demethylation in the early embryo, are resistant to vitamin-C-induced DNA demethylation. Collectively, the results of this study establish vitamin C as a direct regulator of Tet activity and DNA methylation fidelity in ES cells.
Summary
Objective
To examine the true incidence of hemorrhage related to stereo‐electroencephalography (SEEG) procedures. To analyze risk factors associated with the presence of different types of ...hemorrhage in SEEG procedures.
Methods
This was a retrospective, single‐center observational study examining every SEEG implantation performed at our center from 2009 to 2017. This consisted of 549 consecutive SEEG implantations using a variety of stereotactic and imaging techniques. A hemorrhage grading system was applied by a blinded neuroradiologist to every postimplant and postexplant computed tomography (CT) scan. Hemorrhages were classified as asymptomatic or symptomatic based on neurologic deficit seen on examination. Statistical analysis included multivariate regression using relevant preoperative variables to predict the presence of hemorrhage.
Results
One hundred five implantations (19.1%) had any type of hemorrhage seen on postimplant CT. Of these, 93 (16.9%) were asymptomatic and 12 (2.2%) were symptomatic, with 3 implantations (0.6%) resulting in either a permanent deficit (2, 0.4%) or death (1, 0.2%). Male sex, increased number of electrodes, and increasing age were associated with increased risk of postimplant hemorrhage on multivariate analysis. Increasing score in the grading system was related to a statistically significant increase in the likelihood of a symptomatic hemorrhage.
Significance
Detailed examination of every postimplant CT reveals that the total hemorrhage rate appears higher than previously reported. Most of these hemorrhages are small and asymptomatic. Our grading system may be useful to risk stratify these hemorrhages and awaits prospective validation.
Summary
Objective
Stereo‐electroencephalography (SEEG) is a procedure performed for patients with intractable epilepsy in order to anatomically define the epileptogenic zone (EZ) and the possible ...related functional cortical areas. By avoiding the need for large craniotomies and due to its intrinsic precision placement features, SEEG may be associated with fewer complications. Nevertheless, intracerebral electrodes have gained a reputation of excessive invasiveness, with a “relatively high morbidity” associated with their placement. A systematic literature review and meta‐analysis of SEEG complications has not been previously performed. The goal of this study is to quantitatively review the incidence of various surgical complications associated with SEEG electrode implantation in the literature and to provide a summary estimate. This will allow physicians to accurately counsel their patients about the potential complications related to this method of extraoperative invasive monitoring.
Methods
The systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA). We conducted MEDLINE, Scopus, and Web of Science database searches with the search algorithm. We analyzed complication rates using a fixed‐effects model with inverse variance weighting. Calculations for the meta‐analysis and construction of forest plots were completed using an established spreadsheet. The principal summary measures were the effect summary value and 95% confidence intervals (CIs).
Results
The initial 1,901 retrieved citations were reviewed. After removing 787 duplicates, the titles and s of 1,114 publications were screened. At this stage, studies that did not mention the absence or presence of complications following SEEG or that did not fulfill the inclusion criteria in any manner were excluded. After excluding 1,057 citations, the full text was assessed in the resulting 57 articles for eligibility criteria. The most common complications were hemorrhagic (pooled prevalence 1.0%, 95% confidence interval CI 0.6–1.4%) or infectious (pooled prevalence 0.8%, 95% CI 0.3–1.2%). Five mortalities were identified (pooled prevalence 0.3%, 95% CI −0.1–0.6%). Overall, our analysis identified 121 surgical complications related to SEEG insertion and monitoring (pooled prevalence 1.3%, 95% CI 0.9–1.7%).
Significance
This review represents a comprehensive estimation of the actual incidence of complications related to SEEG. We report a rate substantially lower than the complication rates reported for other methods of extraoperative invasive monitoring. These data should alleviate the concerns of some regarding the safety of the “stereotactic” method, allowing a better decision process among the different methods of invasive monitoring and ameliorating the fear associated with the placement of depth electrodes.
Objective
Ultra‐high‐field 7‐Tesla (7T) magnetic resonance imaging (MRI) offers increased signal‐to‐noise and contrast‐to‐noise ratios, which may improve visualization of cortical malformations. We ...aim to assess the clinical value of in vivo structural 7T MRI and its post‐processing for the noninvasive identification of epileptic brain lesions in patients with pharmacoresistant epilepsy and nonlesional 3T MRI who are undergoing presurgical evaluation.
Methods
Sixty‐seven patients were included who had nonlesional 3T MRI by official radiology report. Epilepsy protocols were used for the 3T and 7T acquisitions. Post‐processing of the 7T T1‐weighted magnetization‐prepared two rapid acquisition gradient echoes sequence was performed using the morphometric analysis program (MAP) with comparison to a normal database consisting of 50 healthy controls. Review of 7T was performed by an experienced board‐certified neuroradiologist and at the multimodal patient management conference. The clinical significance of 7T findings was assessed based on intracranial electroencephalography (ICEEG) ictal onset, surgery, postoperative seizure outcomes, and histopathology.
Results
Unaided visual review of 7T detected previously unappreciated subtle lesions in 22% (15/67). When aided by 7T MAP, the total yield increased to 43% (29/67). The location of the 7T‐identified lesion was identical to or contained within the ICEEG ictal onset in 13 of 16 (81%). Complete resection of the 7T‐identified lesion was associated with seizure freedom (P = .03). Histopathology of the 7T‐identified lesions encountered mainly focal cortical dysplasia (FCD). 7T MAP yielded 25% more lesions (6/24) than 3T MAP, and showed improved conspicuity in 46% (11/24).
Significance
Our data suggest a major benefit of 7T with post‐processing for detecting subtle FCD lesions for patients with pharmacoresistant epilepsy and nonlesional 3T MRI.
Dioxygenases of the Ten-Eleven Translocation (TET) family are 5-methylcytosine oxidases that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidation products in DNA. We ...show that Tet1 and Tet2 have distinct roles in regulating 5hmC in mouse embryonic stem cells (mESC). Tet1 depletion diminishes 5hmC levels at transcription start sites (TSS), whereas Tet2 depletion is predominantly associated with decreased 5hmC in gene bodies. Enrichment of 5hmC is observed at the boundaries of exons that are highly expressed, and Tet2 depletion results in substantial loss of 5hmC at these boundaries. In contrast, at promoter/TSS regions, Tet2 depletion results in increased 5hmC, potentially because of the redundant activity of Tet1. Together, the data point to a complex interplay between Tet1 and Tet2 in mESC, and to distinct roles for these two proteins in regulating promoter, exon, and polyadenylation site usage in cells.
Currently, one of the main challenges faced in large metropolitan areas is traffic congestion. To address this problem, adequate traffic control could produce many benefits, including reduced ...pollutant emissions and reduced travel times. If it were possible to characterize the state of traffic by predicting future traffic conditions for optimizing the route of automated vehicles, and if these measures could be taken to preventively mitigate the effects of congestion with its related problems, the overall traffic flow could be improved. This paper performs an experimental study of the traffic distribution in the city of Valencia, Spain, characterizing the different streets of the city in terms of vehicle load with respect to the travel time during rush hour traffic conditions. Experimental results based on realistic vehicular traffic traces from the city of Valencia show that only some street segments fall under the general theory of vehicular flow, offering a good fit using quadratic regression, while a great number of street segments fall under other categories. Although in some cases such discrepancies are related to lack of traffic, injecting additional vehicles shows that significant mismatches still persist. Thus, in this paper we propose an equation to characterize travel times over a segment belonging to the sigmoid family; specifically, we apply logistic regression, being able to significantly improve the curve fitting results for most of the street segments under analysis. Based on our regression results, we performed a clustering analysis of the different street segments, showing that they can be classified into three well-defined categories, which evidences a predictable traffic distribution using the logistic regression throughout the city during rush hours, and allows optimizing the traffic for automated vehicles.
La ecotoxicología estudia los efectos de los contaminantes químicos producidos por acción antropogénica en los diferentes ecosistemas. Las playas, son un ecosistema de interés, ya que en estas ocurre ...una gran cantidad de sedimentación y por lo tanto tienen la capacidad de acumular significativas concentraciones de contaminantes químicos. En Guatemala, las playas del Pacífico son un sujeto ideal para el estudio ecotoxicológico, debido a la fuerte actividad agrícola que ocurre en la parte alta del litoral que causa el uso frecuente de contaminantes químicos. Los contaminantes químicos con más uso son los insecticidas y entre ellos destacan los compuestos organoclorados y el metil paratión, muy utilizados por su alta efectividad. El uso constante de estos compuestos causa que sean depositado en el sedimento que forma las playas, causando que sean absorbidos por organismos de todos los niveles, desde productores primarios como plancton hasta consumidores secundarios como reptiles. Regular el uso de estos compuestos es de interés común, debido a los impactos negativos que pueden acarrear sobre los ecosistemas costeros en donde ocurre una gran actividad tanto comercial, como recreativa por parte de las comunidades costeras. Mitigar el impacto de estos compuestos solo será posible si los actores que inciden en toda el área litoral del Pacífico toman conciencia de la potencial degradación de las playas y la importancia de su función tanto para las actividades antropogénicas diarias como para la convergencia ecológica de las múltiples especies que dependen de las mismas para su supervivencia.
Ten-eleven translocation (TET) enzymes oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine and other oxidized methylcytosines, intermediates in DNA demethylation. In this study, we examine the ...role of TET proteins in regulating Foxp3, a transcription factor essential for the development and function of regulatory T cells (T reg cells), a distinct lineage of CD4(+) T cells that prevent autoimmunity and maintain immune homeostasis. We show that during T reg cell development in the thymus, TET proteins mediate the loss of 5mC in T reg cell-specific hypomethylated regions, including CNS1 and CNS2, intronic cis-regulatory elements in the Foxp3 locus. Similar to CNS2-deficient T reg cells, the stability of Foxp3 expression is markedly compromised in T reg cells from Tet2/Tet3 double-deficient mice. Vitamin C potentiates TET activity and acts through Tet2/Tet3 to increase the stability of Foxp3 expression in TGF-β-induced T reg cells. Our data suggest that targeting TET enzymes with small molecule activators such as vitamin C might increase induced T reg cell efficacy.
The current standard model of language production involves a sensorimotor dorsal stream connecting areas in the temporo‐parietal junction with those in the inferior frontal gyrus and lateral premotor ...cortex. These regions have been linked to various aspects of word production such as phonological processing or articulatory programming, primarily through neuropsychological and functional imaging group studies. Most if not all the theoretical descriptions of this model imply that the same network should be identifiable across individual speakers. We tested this hypothesis by quantifying the variability of activation observed across individuals within each dorsal stream anatomical region. This estimate was based on electrical activity recorded directly from the cerebral cortex with millisecond accuracy in awake epileptic patients clinically implanted with intracerebral depth electrodes for pre‐surgical diagnosis. Each region's activity was quantified using two different metrics—intra‐cerebral evoked related potentials and high gamma activity—at the level of the group, the individual and the recording contact. The two metrics show simultaneous activation of parietal and frontal regions during a picture naming task, in line with models that posit interactive processing during word retrieval. They also reveal different levels of between‐patient variability across brain regions, except in core auditory and motor regions. The independence and non‐uniformity of cortical activity estimated through the two metrics push the current model towards sub‐second and sub‐region explorations focused on individualized language speech production. Several hypotheses are considered for this within‐region heterogeneity.
Standard models of language processing involve a dorsal stream connecting temporal, parietal and frontal regions, each linked to particular aspects of word production—for example, phonological processing or articulatory programming. Most theories imply that the same network should be identifiable across individuals. This hypothesis was tested by quantifying the variability of activation observed across speakers within each region. Two metrics of brain activity recorded intra‐cerebrally in awake epileptic patients revealed diverse levels of variability. Several hypotheses are considered for this within‐region heterogeneity.
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