Genome-wide profiling of histone modifications can reveal not only the location and activity state of regulatory elements, but also the regulatory mechanisms involved in cell-type-specific gene ...expression during development and disease pathology. Conventional assays to profile histone modifications in bulk tissues lack single-cell resolution. Here we describe an ultra-high-throughput method, Paired-Tag, for joint profiling of histone modifications and transcriptome in single cells to produce cell-type-resolved maps of chromatin state and transcriptome in complex tissues. We used this method to profile five histone modifications jointly with transcriptome in the adult mouse frontal cortex and hippocampus. Integrative analysis of the resulting maps identified distinct groups of genes subject to divergent epigenetic regulatory mechanisms. Our single-cell multiomics approach enables comprehensive analysis of chromatin state and gene regulation in complex tissues and characterization of gene regulatory programs in the constituent cell types.
Abstract N -methyl-D-aspartate receptor (NMDAR) hypofunction in parvalbumin-expressing (PV+) inhibitory neurons (INs) may contribute to symptoms in patients with schizophrenia (SZ). This hypothesis ...was inspired by studies in humans involving NMDAR antagonists that trigger SZ symptoms. Animal models of SZ using neuropharmacology and genetic knockouts have successfully replicated some of the key observations in human subjects involving alteration of gamma band oscillations (GBO) observed in electroencephalography and magnetoencephalography signals. However, it remains to be seen if NMDAR hypofunction in PV+ neurons is fundamental to the phenotype observed in these models. In this review, we discuss some of the key computational models of GBO and their predictions in the context of NMDAR hypofunction in INs. While PV+ INs have been the main focus of SZ studies in animal models, we also discuss the implications of NMDAR hypofunction in other types of INs using computational models for GBO modulation in the visual cortex.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
DNA methylation is implicated in mammalian brain development and plasticity underlying learning and memory. We report the genome-wide composition, patterning, cell specificity, and dynamics of DNA ...methylation at single-base resolution in human and mouse frontal cortex throughout their lifespan. Widespread methylome reconfiguration occurs during fetal to young adult development, coincident with synaptogenesis. During this period, highly conserved non-CG methylation (mCH) accumulates in neurons, but not glia, to become the dominant form of methylation in the human neuronal genome. Moreover, we found an mCH signature that identifies genes escaping X-chromosome inactivation. Last, whole-genome single-base resolution 5-hydroxymethylcytosine (hmC) maps revealed that hmC marks fetal brain cell genomes at putative regulatory regions that are CG-demethylated and activated in the adult brain and that CG demethylation at these hmC-poised loci depends on Tet2 activity.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
INTRODUCTIONFew studies have validated the Spanish-language version of the Montreal Cognitive Assessment (MoCA-S) test in Latin American populations. OBJETIVETo evaluate the psychometric properties ...and discriminant validity of the MoCA-S in elderly patients in Santiago de Chile. METHODS172 individuals were grouped according to their clinical diagnosis based on the Clinical Dementia Rating (CDR) scale as follows: amnestic mild cognitive impairment (aMCI; n±24), non-amnestic MCI (naMCI; n±24), mild dementia (n±20), and cognitively normal (n±104). Participants were evaluated with both the MoCA-S and the Mini-Mental State Examination (MMSE) to determine the discriminant validity of the MoCA-S. RESULTSMean age and years of schooling were 73±6 and 11±4 years, respectively, with no significant intergroup differences. The MoCA-S displayed good internal consistency (Cronbach's α: 0.772), high inter-rater reliability (Spearman correlation coefficient: 0.846; P<.01), and high intra-rater reliability (test-retest reliability coefficient: 0.922; P<.001). The MoCA-S was found to be an effective and valid test for detecting aMCI (AUC±0.903) and mild dementia (AUC±0.957); its effectiveness for detecting naMCI was lower (AUC±0.629). The optimal cut-off points for aMCI and mild dementia were<21 and<20, respectively, with sensitivity and specificity rates of 75% and 82% for aMCI and 90% and 86% for mild dementia. The level of education had a great impact on scores: as a result, 2 points were added for patients with less than 8 years of schooling and one point for patients with 8-12 years of schooling (MoCA-S1-2). The MoCA-S1-2 showed significantly greater discriminant validity than the MMSE for differentiating aMCI from dementia. CONCLUSIONSThe MoCA-S1-2 is a short, easy-to-use, and useful test for diagnosing aMCI and mild dementia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Simultaneous profiling of transcriptome and chromatin accessibility within single cells is a powerful approach to dissect gene regulatory programs in complex tissues. However, current tools are ...limited by modest throughput. We now describe an ultra high-throughput method, Paired-seq, for parallel analysis of transcriptome and accessible chromatin in millions of single cells. We demonstrate the utility of Paired-seq for analyzing the dynamic and cell-type-specific gene regulatory programs in complex tissues by applying it to mouse adult cerebral cortex and fetal forebrain. The joint profiles of a large number of single cells allowed us to deconvolute the transcriptome and open chromatin landscapes in the major cell types within these brain tissues, infer putative target genes of candidate enhancers, and reconstruct the trajectory of cellular lineages within the developing forebrain.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We evaluated the risk of sampling errors in specimens of biopsy size, which may be caused by heterogeneous overexpression of Her2/neu in gastric cancer (GC).
The study cohort comprised 454 ...gastrectomy patients with adenocarcinoma of the stomach or esophago-gastric junction. Tissue micro-arrays (TMAs) served as ‘biopsy procedure’ and were generated from formalin-fixed and paraffin-embedded tissue: five tissue cylinders were collected randomly from each tumor, rendering 2230 core cylinders. These were compared with 454 whole tissue sections obtained from the same paraffin blocks. Her2/neu expression and gene amplification were analyzed by immunohistochemistry and in situ hybridization. The Her2/neu status was determined according to GC scoring system by two independent observers.
In whole tissue sections, 37 (8.1%; observer 1) and 38 (8.4%; observer 2) of the GCs, and in the corresponding TMAs, 28 (6.3%; observer 1) and 28 (6.3%; observer 2) of the GCs were classified as Her2/neu-positive (kappa value 98.5% and 96.2%; P < 0001). Comparison of whole tissue sections with corresponding TMAs showed a false-negative rate of 24% and a false-positive rate of 3% for TMAs.
Assessment of the Her2/neu status in tissue biopsies carries a significant risk of sampling errors, thereby rendering patients unsuitable for treatment with trastuzumab.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Postmortem and functional imaging studies of patients with psychiatric disorders, including schizophrenia, are consistent with a dysfunction of interneurons leading to compromised inhibitory control ...of network activity. Parvalbumin (PV)-expressing, fast-spiking interneurons interacting with pyramidal neurons generate cortical gamma oscillations (30-80 Hz) that synchronize cortical activity during cognitive processing. In postmortem studies of schizophrenia patients, these interneurons show reduced PV and glutamic acid decarboxylase 67 (GAD67), an enzyme that synthesizes GABA, but the consequences of this downregulation are unclear. We developed a biophysically realistic and detailed computational model of a cortical circuit including asynchronous release from GABAergic interneurons to investigate how reductions in PV and GABA affect gamma oscillations induced by sensory stimuli. Networks with reduced GABA were disinhibited and had altered gamma oscillations in response to stimulation; PV-deficient GABA synapses had increased asynchronous release of GABA, which decreased the level of excitation and reduced gamma-band activity. Combined reductions of PV and GABA resulted in a diminished gamma-band oscillatory activity in response to stimuli, similar to that observed in schizophrenia patients. Our results suggest a mechanism by which reduced GAD67 and PV in fast-spiking interneurons may contribute to cortical dysfunction in schizophrenia and related psychiatric disorders.
To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD).
Cox proportional hazards models were used to test associations between prevalent dementia and risk ...of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study-Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer.
The presence of any AD (pure AD + mixed AD/VaD; hazard ratio HR = 0.41, 95% confidence interval CI = 0.20-0.84) and pure AD (HR = 0.31, 95% CI = 0.12-0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52-0.997) and pure AD (HR = 0.57; 95% CI = 0.36-0.90) among white subjects after adjustment for demographics, number of APOE epsilon4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD.
In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.
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