DNA methylation is a major epigenetic modification that regulates gene expression. Dnmt1, the maintenance DNA methylation enzyme, is abundantly expressed in the adult brain and is mainly located in the nuclear compartment, where it has access to chromatin. Hypomethylation of CpG islands at intron 1 of the SNCA gene has recently been reported to result in overexpression of ␣-synuclein in Parkinson disease (PD) and related disorders. We therefore investigated the mechanisms underlying altered DNA methylation in PD and dementia with Lewy bodies (DLB). We present evidence of reduction of nuclear Dnmt1 levels in human postmortem brain samples from PD and DLB patients as well as in the brains of ␣-synuclein transgenic mice models. Furthermore, sequestration of Dnmt1 in the cytoplasm results in global DNA hypomethylation in human and mouse brains, involving CpG islands upstream of SNCA, SEPW1, and PRKAR2A genes. We report that association of Dnmt1 and ␣-synuclein might mediate aberrant subcellular localization of Dnmt1. Nuclear Dnmt1 levels were partially rescued by overexpression of Dnmt1 in neuronal cell cultures and in ␣-synuclein transgenic mice brains. Our results underscore a novel mechanism for epigenetic dysregulation in Lewy body diseases, which might underlie the decrease in DNA methylation reported for PD and DLB. Parkinson disease (PD)2 and dementia with Lewy bodies (DLB) belong to a heterogeneous group of neurodegenerative disorders known as Lewy body diseases, which are characterized by ␣-synuclein (␣-syn) accumulation in Lewy body structures (1, 2). The most striking pathological feature of PD is the loss of dopaminergic neurons in the substantia nigra, although neurodegeneration has been also reported to occur in the cortex. In DLB, non-motor cognitive alterations appear before parkinsonism and ␣-syn accumulates mainly in the limbic system and neocortical areas, suggesting that these structures have an important role in disease (3). At the molecular level, accumulation of misfolded ␣-syn affects mitochondrial function, autophagy (4), and the expression of several functional groups of genes (5, 6), although the molecular basis of transcriptional dysregulation remain elusive.Proper gene expression is crucial for the cell, and therefore, it is tightly regulated by the binding of regulatory proteins to promoter regions and by the epigenetic remodeling of the chromatin structure by DNA methylation and histone modifications. Although the traditional concept of epigenetics refers to stable and heritable changes associated with cell division and development, there is mounting evidence supporting that DNA methylation is dynamically regulated in postmitotic neurons, having crucial roles in memory formation and synaptic plasticity (7). Altered epigenetic mechanisms have also been associated with neurological disorders, including Rett syndrome, autism, schizophrenia, and Alzheimer, Huntington, and Parkinson diseases (8). The relevance of DNA methylation in PD pathology was highlighted recently by two studies showin...

Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome that affects children and adults. Individuals with NF1 are at high risk for central nervous system neoplasms including gliomas. The purpose of this review is to discuss the spectrum of intracranial gliomas arising in individuals with NF1 with a focus on recent preclinical and clinical data. In this review, possible mechanisms of gliomagenesis are discussed, including the contribution of different signaling pathways and tumor microenvironment. Furthermore, we discuss the recent notable advances in the developing therapeutic landscape for NF1-associated gliomas including clinical trials and collaborative efforts.

Background Primary intestinal immunity through viral replication of live oral vaccine is key to interrupt poliovirus transmission. We assessed viral fecal shedding from infants administered Sabin monovalent poliovirus type 2 vaccine (mOPV2) or low- and high-doses of two novel OPV2 (nOPV2) vaccine candidates. Methods In two randomized clinical trials in Panama, a control mOPV2 study (October 2015 to April 2016) and nOPV2 study (September 2018 to October 2019), 18-week-old bOPV/IPV-vaccinated infants received one or two study vaccinations 28 days apart. Stools were assessed for poliovirus RNA by PCR and live virus by culture for 28 days postvaccination. Results Shedding data were available from 621 initially RT-PCR negative infants (91 mOPV2, 265 nOPV2-c1, 265 nOPV2-c2 recipients). Seven days after dose 1, 64.3% of mOPV2 recipients and 31.3–48.5% of nOPV2 recipients across groups shed infectious type 2 virus. Respective rates 7 days after dose 2 decreased to 33.3% and 12.9–22.7%, showing induction of intestinal immunity. Shedding of both nOPV2 candidates ceased at similar or faster rates than mOPV2. Conclusions Viral shedding of either nOPV candidate was similar or decreased relative to mOPV2, and all vaccines showed indications that the vaccine virus was replicating sufficiently to induce primary intestinal mucosal immunity.

Background Low-grade gliomas cause significant neurological morbidity by brain invasion. There is no universally accepted objective technique available for detection of enlargement of low-grade gliomas in the clinical setting; subjective evaluation by clinicians using visual comparison of longitudinal radiological studies is the gold standard. The aim of this study is to determine whether a computer-assisted diagnosis (CAD) method helps physicians detect earlier growth of low-grade gliomas. Methods and findings We reviewed 165 patients diagnosed with grade 2 gliomas, seen at the University of Alabama at Birmingham clinics from 1 July 2017 to 14 May 2018. MRI scans were collected during the spring and summer of 2018. Fifty-six gliomas met the inclusion criteria, including 19 oligodendrogliomas, 26 astrocytomas, and 11 mixed gliomas in 30 males and 26 females with a mean age of 48 years and a range of follow-up of 150.2 months (difference between highest and lowest values). None received radiation therapy. We also studied 7 patients with an imaging abnormality without pathological diagnosis, who were clinically stable at the time of retrospective review (14 May 2018). This study compared growth detection by 7 physicians aided by the CAD method with retrospective clinical reports. The tumors of 63 patients (56 + 7) in 627 MRI scans were digitized, including 34 grade 2 gliomas with radiological progression and 22 radiologically stable grade 2 gliomas. The CAD method consisted of tumor segmentation, computing volumes, and pointing to growth by the online abrupt change-of-point method, which considers only past measurements. Independent scientists have evaluated the segmentation method. In 29 of the 34 patients with progression, the median time to growth detection was only 14 months for CAD compared to 44 months for current standard of care radiological evaluation ( p < 0.001). Using CAD, accurate detection of tumor enlargement was possible with a median of only 57% change in the tumor volume as compared to a median of 174% change of volume necessary to diagnose tumor growth using standard of care clinical methods ( p < 0.001). In the radiologically stable group, CAD facilitated growth detection in 13 out of 22 patients. CAD did not detect growth in the imaging abnormality group. The main limitation of this study was its retrospective design; nevertheless, the results depict the current state of a gold standard in clinical practice that allowed a significant increase in tumor volumes from baseline before detection. Such large increases in tumor volume would not be permitted in a prospective design. The number of glioma patients ( n = 56) is a limitation; however, it is equivalent to the number of patients in phase II clinical trials. Conclusions The current practice of visual comparison of longitudinal MRI scans is associated with significant delays in detecting g...