Identification of candidate DNA methylation biomarkers related to Alzheimer's disease risk by integrating genome and blood methylome data.

Alzheimer disease (AD) is a common neurodegenerative disease with a late onset. It is critical to identify novel blood-based DNA methylation biomarkers to better understand the extent of the molecular pathways affected in AD. Two sets of blood DNA methylation genetic prediction models developed using different reference panels and modelling strategies were leveraged to evaluate associations of genetically predicted DNA methylation levels with AD risk in 111,326 (46,828 proxy) cases and 677,663 controls.

The Complexity of Two Colouring Games.

We consider two variants of on graphs. In these games, two players alternate colouring uncoloured vertices (from a choice of colours) of a pair of isomorphic graphs while respecting the properness and the orthogonality of the partial colourings. In the , the first player unable to move loses.

Sex Differences in the Molecular Programs of Pancreatic Cells Contribute to the Differential Risks of Type 2 Diabetes.

Epidemiology studies demonstrate that women are at a significantly lower risk of developing type 2 diabetes (T2D) compared to men. However, the molecular basis of this risk difference is not well understood. In this study, we examined the sex differences in the genetic programs of pancreatic endocrine cells.

Differentiation of Amyloid Plaques Between Alzheimer's Disease and Non-Alzheimer's Disease Individuals Based on Gray-Level Co-occurrence Matrix Texture Analysis.

Amyloid plaques, one of the main hallmarks of Alzheimer's disease (AD), are classified into diffuse (associated with cognitive impairment) and dense-core types (a common finding in brains of people without Alzheimer's disease (non-AD) and without impaired cognitive function) based on their morphology. We tried to determine the usability of gray-level co-occurrence matrix (GLCM) texture parameters of homogeneity and heterogeneity for the differentiation of amyloid plaque images obtained from AD and non-AD individuals. Images of amyloid-β (Aβ) immunostained brain tissue samples were obtained from the Aging, Dementia and Traumatic Brain Injury Project.

Sex-biased hippocampal pathology in the 5XFAD mouse model of Alzheimer's disease: A multi-omic analysis.

Alzheimer's disease is a progressive neurodegenerative disorder and the most common form of dementia. Like many neurological disorders, Alzheimer's disease has a sex-biased epidemiological profile, affecting approximately twice as many women as men. The cause of this sex difference has yet to be elucidated.

Stability of Wake-Sleep Cycles Requires Robust Degradation of the PERIOD Protein.

Robustness in biology is the stability of phenotype under diverse genetic and/or environmental perturbations. The circadian clock has remarkable stability of period and phase that-unlike other biological oscillators-is maintained over a wide range of conditions. Here, we show that the high fidelity of the circadian system stems from robust degradation of the clock protein PERIOD.

Loss of Brap Results in Premature G1/S Phase Transition and Impeded Neural Progenitor Differentiation.

Cells initiate fate decisions during G1 phase by converting extracellular signals into distinctive cell cycle kinetics. The DNA replication timing is determined in G1 phase; lengthened G1 and hastened S phases correlate with increased neurogenic propensity of neural progenitor cells (NPCs), although the underlying molecular control remains elusive. Here, we report that proper G1 phase completion in NPCs requires Brap, a Ras-Erk signaling modulator with ubiquitin E3 ligase activity.

The stability of the transcriptome during the estrous cycle in four regions of the mouse brain.

We analyzed the transcriptome of the C57BL/6J mouse hypothalamus, hippocampus, neocortex, and cerebellum to determine estrous cycle-specific changes in these four brain regions. We found almost 16,000 genes are present in one or more of the brain areas but only 210 genes, ∼1.3%, are significantly changed as a result of the estrous cycle.

Sex differences in the molecular signature of the developing mouse hippocampus.

Background: A variety of neurological disorders, including Alzheimer's disease, Parkinson's disease, major depressive disorder, dyslexia and autism, are differentially prevalent between females and males. To better understand the possible molecular basis for the sex-biased nature of neurological disorders, we used a developmental series of female and male mice at 1, 2, and 4 months of age to assess both mRNA and protein in the hippocampus with RNA-sequencing and mass-spectrometry, respectively.

Results: The transcriptomic analysis identifies 2699 genes that are differentially expressed between animals of different ages.

Bioinformatic analysis reveals the expression of unique transcriptomic signatures in Zika virus infected human neural stem cells.

Background: The single-stranded RNA Flavivirus, Zika virus (ZIKV), has recently re-emerged and spread rapidly across the western hemisphere's equatorial countries, primarily through Aedes mosquito transmission. While symptoms in adult infections appear to be self-limiting and mild, severe birth defects, such as microcephaly, have been linked to infection during early pregnancy. Recently, Tang et al.

Transcriptomic analysis of the hippocampus from six inbred strains of mice suggests a basis for sex-specific susceptibility and severity of neurological disorders.

Identifying sex differences in gene expression within the brain is critical for determining why multiple neurological and behavioral disorders differentially affect males and females. Several disorders are more common or severe in males (e.g.

An Examination of Dynamic Gene Expression Changes in the Mouse Brain During Pregnancy and the Postpartum Period.

The developmental transition to motherhood requires gene expression changes that alter the brain to drive the female to perform maternal behaviors. We broadly examined the global transcriptional response in the mouse maternal brain, by examining four brain regions: hypothalamus, hippocampus, neocortex, and cerebellum, in virgin females, two pregnancy time points, and three postpartum time points. We find that overall there are hundreds of differentially expressed genes, but each brain region and time point shows a unique molecular signature, with only 49 genes differentially expressed in all four regions.

Differential effects of acellular embryonic matrices on pluripotent stem cell expansion and neural differentiation.

Extracellular matrices (ECM) derived from pluripotent stem cells (PSCs) provide a unique tissue microenvironment that can direct cellular differentiation and tissue regeneration, and rejuvenate aged progenitor cells. The unlimited growth capacity of PSCs allows for the scalable generation of PSC-secreted ECMs. Therefore, the derivation and characterization of PSC-derived ECMs is of critical importance in drug screening, disease modeling and tissue regeneration.

A multi-resource data integration approach: identification of candidate genes regulating cell proliferation during neocortical development.

Neurons of the mammalian neocortex are produced by proliferating cells located in the ventricular zone (VZ) lining the lateral ventricles. This is a complex and sequential process, requiring precise control of cell cycle progression, fate commitment and differentiation. We have analyzed publicly available databases from mouse and human to identify candidate genes that are potentially involved in regulating early neocortical development and neurogenesis.

An integrated approach to design novel therapeutic interventions for demyelinating disorders.

Therapeutic strategies are often based on two general principles: interference with the pathogenic process and repair of the damaged tissues. Recent studies, however, have suggested that several pathological conditions may result from the interplay between genetic susceptibility traits and environmental influences that, by modulating the epigenome, also affect disease onset and progression. Based on lessons from neural development, it is conceivable that new lines of preventive and possibly therapeutic intervention might be developed to modulate disease onset or decrease the severity of the symptoms.

Cdk5rap2 exposes the centrosomal root of microcephaly syndromes.

Autosomal recessive primary microcephaly (MCPH) is characterized by small brain size as a result of deficient neuron production in the developing cerebral cortex. Although MCPH is a rare disease, the questions surrounding its etiology strike at the core of stem cell biology. The seven genes implicated in MCPH all encode centrosomal proteins and disruption of the MCPH gene Cdk5rap2 in mice revealed its role in neural progenitor proliferation and in maintaining normal centriole replication control.

Identification of a Chr 11 quantitative trait locus that modulates proliferation in the rostral migratory stream of the adult mouse brain.

Neuron production takes place continuously in the rostral migratory stream (RMS) of the adult mammalian brain. The molecular mechanisms that regulate progenitor cell division and differentiation in the RMS remain largely unknown. Here, we surveyed the mouse genome in an unbiased manner to identify candidate gene loci that regulate proliferation in the adult RMS.

Neocortical neurogenesis: morphogenetic gradients and beyond.

Each of the five cellular layers of the cerebral neocortex is composed of a specific number of a single predominant 'class' of projection neuron. The projection neuron class is defined by its unique morphology and axonal projections to other areas of the brain. Precursor cell populations lining the embryonic lateral ventricles produce the projection neurons.

Unsupervised selection of highly coexpressed and noncoexpressed genes using a consensus clustering approach.

In this paper we explore the concept of consensus clustering to identify, within a set of differentially expressed genes, a subset of genes that are either highly coexpressed or highly noncoexpressed based on the hypothesis that this subset would serve as a better starting point for further analyses. A number of core clustering methods form the basis for the assertion of an agreement matrix (AM) characterizing the level of coexpression between any two probesets. In order to overcome the limitations of using a single distance metric, we explore different metrics and examine the sensitivity of the AM as a function of the input number of clusters to find a suggestive number of clusters that best describes a particular dataset.

Distribution of EphA5 receptor protein in the developing and adult mouse nervous system.

The EphA5 receptor tyrosine kinase plays key roles in axon guidance during development. However, the presence of EphA5 protein in the nervous system has not been fully characterized. To examine EphA5 localization better, mutant mice, in which the EphA5 cytoplasmic domain was replaced with beta-galactosidase, were analyzed for both temporal and regional changes in the distribution of EphA5 protein in the developing and adult nervous system.

Genetics of the hippocampal transcriptome in mouse: a systematic survey and online neurogenomics resource.

Differences in gene expression in the CNS influence behavior and disease susceptibility. To systematically explore the role of normal variation in expression on hippocampal structure and function, we generated an online microarray database for a diverse panel of strains of mice, including most common inbred strains and numerous recombinant inbred lines (www.genenetwork.

Radiation, retardation and the developing brain: time is the crucial variable.

Background: Widespread radiation is a threat unique to the modern world. A recent report reveals that sub-clinical damage to human foetuses between 8 and 25 weeks of gestation can result in cognitive deficits still manifest 16-18 years after birth. These previously unrecognised, long-term effects are apparently produced by a relatively short pulse of exposure to radioactive fallout at levels that were previously thought not to be deleterious.