Genetic association of CDC2 with cerebrospinal fluid tau in Alzheimer's disease

We have recently reported that a polymorphism in the cell division cycle (CDC2) gene, designated Ex6 + 7I/D, is associated with Alzheimer's disease (AD). The CDC2 gene is located on chromosome 10q21.1 close to the marker D10S1225 linked to AD. Active cdc2 accumulates in neurons containing neurofibrillary tangles (NFT), a process that can precede the formation of NFT. Therefore, CDC2 is a promising candidate susceptibility gene for AD. We investigated the possible effects of the CDC2 polymorphism on cerebrospinal fluid (CSF) biomarkers in AD patients. CDC2 genotypes were evaluated in relation to CSF protein levels of total tau, phospho-tau and beta-amyloid (1-42) in AD patients and control individuals, and in relation to the amount of senile plaques and NFT in the frontal cortex and in the hippocampus in patients with autopsy-proven AD and controls. The CDC2 Ex6 + 7I allele was associated with a gene dose-dependent increase of CSF total tau levels (F-2,F- 626 = 7.0, p = 0.001) and the homozygous CDC2Ex6 +7II genotype was significantly more frequent among AD patients compared to controls (p = 0.006, OR = 1.57, 95% CI 1.13-2.17). Our results provide further evidence for an involvement of cdc2 in the pathogenesis of AD. Copyright (C) 2005 S. Karger AG, Basel

Particle approximation of the one dimensional Keller-Segel equation, stability and rigidity of the blow-up

We investigate a particle system which is a discrete and deterministic approximation of the one-dimensional Keller-Segel equation with a logarithmic potential. The particle system is derived from the gradient flow of the homogeneous free energy written in Lagrangian coordinates. We focus on the description of the blow-up of the particle system, namely: the number of particles involved in the first aggregate, and the limiting profile of the rescaled system. We exhibit basins of stability for which the number of particles is critical, and we prove a weak rigidity result concerning the rescaled dynamics. This work is complemented with a detailed analysis of the case where only three particles interact

Classical relativistic statistical mechanics: The case of a hot dilute plasma

Starting from predictive relativistic mechanics we develop a classical relativistic statistical mechanics. For a system of N particles, the basic distribution function depends, in addition to the 6N coordinates and velocities, on N times, instead of a single one as in the usual statistical mechanics. This generalized distribution function obeys N (instead of 1) continuity equations, which give rise to N Liouville equations in the case of a dilute plasma (i.e., to lowest, nonzero order in the charges). Hence, the Bogoliubov-Born-Green-Kirkwood-Yvon hierarchy for the reduced generalized distribution functions is derived. A relativistic Vlasov equation is obtained in this way. Thermal equilibrium is then considered for a dilute plasma. The calculation is explicitly worked out for a weakly relativistic plasma, up to order 1/c2, and known results are recovered

Efficiently identifying genome-wide changes with next-generation sequencing data

We propose a new and effective statistical framework for identifying genome-wide differential changes in epigenetic marks with ChIP-seq data or gene expression with mRNA-seq data, and we develop a new software tool EpiCenter that can efficiently perform data analysis. The key features of our framework are: (i) providing multiple normalization methods to achieve appropriate normalization under different scenarios, (ii) using a sequence of three statistical tests to eliminate background regions and to account for different sources of variation and (iii) allowing adjustment for multiple testing to control false discovery rate (FDR) or family-wise type I error. Our software EpiCenter can perform multiple analytic tasks including: (i) identifying genome-wide epigenetic changes or differentially expressed genes, (ii) finding transcription factor binding sites and (iii) converting multiple-sample sequencing data into a single read-count data matrix. By simulation, we show that our framework achieves a low FDR consistently over a broad range of read coverage and biological variation. Through two real examples, we demonstrate the effectiveness of our framework and the usages of our tool. In particular, we show that our novel and robust ‘parsimony’ normalization method is superior to the widely-used ‘tagRatio’ method. Our software EpiCenter is freely available to the public

Genotype–phenotype correlations in individuals with pathogenic RERE variants

Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss-of-function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine-rich region in the Atrophin-1 domain. We have also identified a recurrent two-amino-acid duplication in this region that is associated with the development of a CHARGE syndrome-like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7

Genotype–phenotype correlations in individuals with pathogenic RERE variants

Heterozygous variants in the arginine‐glutamic acid dipeptide repeats gene (RERE) have been shown to cause neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH). Here, we report nine individuals with NEDBEH who carry partial deletions or deleterious sequence variants in RERE. These variants were found to be de novo in all cases in which parental samples were available. An analysis of data from individuals with NEDBEH suggests that point mutations affecting the Atrophin‐1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, renal anomalies, and sensorineural hearing loss when compared with loss‐of‐function variants that are likely to lead to haploinsufficiency. A high percentage of RERE pathogenic variants affect a histidine‐rich region in the Atrophin‐1 domain. We have also identified a recurrent two‐amino‐acid duplication in this region that is associated with the development of a CHARGE syndrome‐like phenotype. We conclude that mutations affecting RERE result in a spectrum of clinical phenotypes. Genotype–phenotype correlations exist and can be used to guide medical decision making. Consideration should also be given to screening for RERE variants in individuals who fulfill diagnostic criteria for CHARGE syndrome but do not carry pathogenic variants in CHD7.We describe nine unrelated individuals who carry partial deletions or putatively deleterious sequence variants in RERE. An analysis of clinical and molecular data from individuals with mutations affecting RERE suggests the existence of novel genotype‐phenotype correlations and demonstrates that a high percentage of RERE pathogenic variants affect a histidine‐rich region in the Atrophin‐1 domain. We have also identified a recurrent two‐amino‐acid duplication in this region that is associated with the development of a CHARGE syndrome‐like phenotype.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143789/1/humu23400_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143789/2/humu23400.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/143789/3/humu23400-sup-0001-SuppMat.pd

MAP3K4/CBP-Regulated H2B Acetylation Controls Epithelial-Mesenchymal Transition in Trophoblast Stem Cells

Epithelial stem cells self-renew while maintaining multipotency, but the dependence of stem cell properties on maintenance of the epithelial phenotype is unclear. We previously showed that trophoblast stem (TS) cells lacking the protein kinase MAP3K4 maintain properties of both stemness and epithelial-mesenchymal transition (EMT). Here, we show that MAP3K4 controls the activity of the histone acetyltransferase CBP, and that acetylation of histones H2A and H2B by CBP is required to maintain the epithelial phenotype. Combined loss of MAP3K4/CBP activity represses expression of epithelial genes and causes TS cells to undergo EMT while maintaining their self-renewal and multipotency properties. The expression profile of MAP3K4 deficient TS cells defines an H2B acetylation regulated gene signature that closely overlaps with that of human breast cancer cells. Taken together, our data define an epigenetic switch that maintains the epithelial phenotype in TS cells and reveal previously unrecognized genes potentially contributing to breast cancer