Cell-type-specific effects of age and sex on human cortical neurons.

Altered transcriptional and epigenetic regulation of brain cell types may contribute to cognitive changes with advanced age. Using single-nucleus multi-omic DNA methylation and transcriptome sequencing (snmCT-seq) in frontal cortex from young adult and aged donors, we found widespread age- and sex-related variation in specific neuron types. The proportion of inhibitory SST- and VIP-expressing neurons was reduced in aged donors. Excitatory neurons had more profound age-related changes in their gene expression and DNA methylation than inhibitory cells. Hundreds of genes involved in synaptic activity, including EGR1, were less expressed in aged adults. Genes located in subtelomeric regions increased their expression with age and correlated with reduced telomere length. We further mapped cell-type-specific sex differences in gene expression and X-inactivation escape genes. Multi-omic single-nucleus epigenomes and transcriptomes provide new insight into the effects of age and sex on human neurons.

Brain-wide correspondence of neuronal epigenomics and distant projections.

Single-cell analyses parse the brain's billions of neurons into thousands of 'cell-type' clusters residing in different brain structures1. Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific cell types. Here we used epi-retro-seq2 to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets (225 source-to-target combinations) across the whole mouse brain. We highlight uses of these data for interrogating principles relating projection types to transcriptomics and epigenomics, and for addressing hypotheses about cell types and connections related to genetics. We provide an overall synthesis with 926 statistical comparisons of discriminability of neurons projecting to each target for every source. We integrate this dataset into the larger BRAIN Initiative Cell Census Network atlas, composed of millions of neurons, to link projection cell types to consensus clusters. Integration with spatial transcriptomics further assigns projection-enriched clusters to smaller source regions than the original dissections. We exemplify this by presenting in-depth analyses of projection neurons from the hypothalamus, thalamus, hindbrain, amygdala and midbrain to provide insights into properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription-factor-binding motifs, and neurotransmitter use.

Single-cell DNA methylation and 3D genome architecture in the human brain.

Delineating the gene-regulatory programs underlying complex cell types is fundamental for understanding brain function in health and disease. Here, we comprehensively examined human brain cell epigenomes by probing DNA methylation and chromatin conformation at single-cell resolution in 517 thousand cells (399 thousand neurons and 118 thousand non-neurons) from 46 regions of three adult male brains. We identified 188 cell types and characterized their molecular signatures. Integrative analyses revealed concordant changes in DNA methylation, chromatin accessibility, chromatin organization, and gene expression across cell types, cortical areas, and basal ganglia structures. We further developed single-cell methylation barcodes that reliably predict brain cell types using the methylation status of select genomic sites. This multimodal epigenomic brain cell atlas provides new insights into the complexity of cell-type-specific gene regulation in adult human brains.

Validation of the Indonesian Version of the Asian Diabetes Quality of Life Questionnaire.

BACKGROUND: quality of life has been identified as the goal of therapy especially in patient with chronic disease such as type 2 diabetes mellitus. Quality of life measurement requires an instrument that was specifically developed in accordance with socio-cultural background of the measured population. The aim of this study was to adapt Asian Diabetes Quality of Life Questionnaire so it can be used in Indonesia as valid and reliable tool. METHODS: Asian Diabetes Quality of Life Questionnaire was translated and adapted by group of experts, then validity and reliability tests were conducted on type 2 diabetes mellitus patients at Dr. Hasan Sadikin General Hospital, Bandung. Construct validity was analyzed using correlation test between score of each item and total score. Reliability was measured using test-retest method and internal consistency represented in Cronbach's alpha score. RESULTS: validity test showed significant correlation (p-value ≤0.05) between score of each item and total score across all domains with moderate to very strong correlation (r: 0.496-0.956). Reliability test using test-retest method showed no significant difference between Test I and II results (p-value >0.05) with very strong correlation (r: 0.830-0.975) and internal consistency yielded Cronbach's alpha scores of  ≥ 0.07 for all domains. CONCLUSION: Indonesian version of Asian DQOL is a valid and reliable tool to measure quality of life of type 2 diabetes mellitus patients.