Comprehensive single-cell aging atlas of healthy mammary tissues reveals shared epigenomic and transcriptomic signatures of aging and cancer.

Aging is the greatest risk factor for breast cancer; however, how age-related cellular and molecular events impact cancer initiation is unknown. In this study, we investigated how aging rewires transcriptomic and epigenomic programs of mouse mammary glands at single-cell resolution, yielding a comprehensive resource for aging and cancer biology. Aged epithelial cells exhibit epigenetic and transcriptional changes in metabolic, pro-inflammatory and cancer-associated genes.

Distinct baseline immune characteristics associated with responses to conjugated and unconjugated pneumococcal polysaccharide vaccines in older adults.

Pneumococcal infections cause serious illness and death among older adults. The capsular polysaccharide vaccine PPSV23 and conjugated alternative PCV13 can prevent these infections; yet, underlying immunological responses and baseline predictors remain unknown. We vaccinated 39 older adults (>60 years) with PPSV23 or PCV13 and observed comparable antibody responses (day 28) and plasmablast transcriptional responses (day 10); however, the baseline predictors were distinct.

Baseline immune states (BIS) associated with vaccine responsiveness and factors that shape the BIS.

Vaccines are among the greatest inventions in medicine, leading to the elimination or control of numerous diseases, including smallpox, polio, measles, rubella, and, most recently, COVID-19. Yet, the effectiveness of vaccines varies among individuals. In fact, while some recipients mount a robust response to vaccination that protects them from the disease, others fail to respond.

Epigenetic memory of coronavirus infection in innate immune cells and their progenitors.

Inflammation can trigger lasting phenotypes in immune and non-immune cells. Whether and how human infections and associated inflammation can form innate immune memory in hematopoietic stem and progenitor cells (HSPC) has remained unclear. We found that circulating HSPC, enriched from peripheral blood, captured the diversity of bone marrow HSPC, enabling investigation of their epigenomic reprogramming following coronavirus disease 2019 (COVID-19).

Distinct baseline immune characteristics associated with responses to conjugated and unconjugated pneumococcal polysaccharide vaccines in older adults.

Pneumococcal infections cause serious illness and death among older adults. A capsular polysaccharide vaccine PPSV23 (Pneumovax) and a conjugated polysaccharide vaccine PCV13 (Prevnar) are used to prevent these infections, yet underlying responses, and baseline predictors remain unknown. We recruited and vaccinated 39 older adults (>60 years) with PPSV23 or PCV13.

Challenges and opportunities for modeling aging and cancer.

Age is among the main risk factors for cancer, and any cancer study in adults is faced with an aging tissue and organism. Yet, pre-clinical studies are carried out using young mice and are not able to address the impact of aging and associated comorbidities on disease biology and treatment outcomes. Here, we discuss the limitations of current mouse cancer models and suggest strategies for developing novel models to address these major gaps in knowledge and experimental approaches.

The effect of COVID-19 vaccinations on menstrual cycle and serum anti-Mullerian hormone levels in reproductive age women.

The aim of this prospective cohort study was to investigate the effect of coronavirus disease 2019 (COVID-19) vaccinations on menstrual cycle and ovarian reserve in reproductive aged-women. Health care providers ( = 258) vaccinated with inactivated (CoronaVac) and mRNA based (Pfizer-BioNTech®) COVID-19 vaccines were included. All subjects completed a gynaecological and menstrual history questionnaire and Anti-Mullerian Hormone (AMH) levels were measured in serum samples collected before first vaccination and at 1, 3, 6 and 9 months.

Concomitant inhibition of PPARγ and mTORC1 induces the differentiation of human monocytes into highly immunogenic dendritic cells.

Monocytes can differentiate into macrophages (Mo-Macs) or dendritic cells (Mo-DCs). The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the differentiation of monocytes into Mo-Macs, while the combination of GM-CSF/interleukin (IL)-4 is widely used to generate Mo-DCs for clinical applications and to study human DC biology. Here, we report that pharmacological inhibition of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) in the presence of GM-CSF and the absence of IL-4 induces monocyte differentiation into Mo-DCs.

Transcriptional activation of Jun and Fos members of the AP-1 complex is a conserved signature of immune aging that contributes to inflammaging.

Diverse mouse strains have different health and life spans, mimicking the diversity among humans. To capture conserved aging signatures, we studied long-lived C57BL/6J and short-lived NZO/HILtJ mouse strains by profiling transcriptomes and epigenomes of immune cells from peripheral blood and the spleen from young and old mice. Transcriptional activation of the AP-1 transcription factor complex, particularly Fos, Junb, and Jun genes, was the most significant and conserved aging signature across tissues and strains.

Network Topology of Biological Aging and Geroscience-Guided Approaches to COVID-19.

Aging has emerged as the greatest and most prevalent risk factor for the development of severe COVID-19 infection and death following exposure to the SARS-CoV-2 virus. The presence of multiple co-existing chronic diseases and conditions of aging further enhances this risk. Biological aging not only enhances the risk of chronic diseases, but the presence of such conditions further accelerates varied biological processes or "hallmarks" implicated in aging.

CoRE-ATAC: A deep learning model for the functional classification of regulatory elements from single cell and bulk ATAC-seq data.

Cis-Regulatory elements (cis-REs) include promoters, enhancers, and insulators that regulate gene expression programs via binding of transcription factors. ATAC-seq technology effectively identifies active cis-REs in a given cell type (including from single cells) by mapping accessible chromatin at base-pair resolution. However, these maps are not immediately useful for inferring specific functions of cis-REs.

Functional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation.

Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs) at >250 loci in the human genome to type 2 diabetes (T2D) risk. For each locus, identifying the functional variant(s) among multiple SNPs in high linkage disequilibrium is critical to understand molecular mechanisms underlying T2D genetic risk. Using massively parallel reporter assays (MPRA), we test the cis-regulatory effects of SNPs associated with T2D and altered in vivo islet chromatin accessibility in MIN6 β cells under steady state and pathophysiologic endoplasmic reticulum (ER) stress conditions.

AMULET: a novel read count-based method for effective multiplet detection from single nucleus ATAC-seq data.

Detecting multiplets in single nucleus (sn)ATAC-seq data is challenging due to data sparsity and limited dynamic range. AMULET (ATAC-seq MULtiplet Estimation Tool) enumerates regions with greater than two uniquely aligned reads across the genome to effectively detect multiplets. We evaluate the method by generating snATAC-seq data in the human blood and pancreatic islet samples.

Single Cell Analysis of Blood Mononuclear Cells Stimulated Through Either LPS or Anti-CD3 and Anti-CD28.

Immune cell activation assays have been widely used for immune monitoring and for understanding disease mechanisms. However, these assays are typically limited in scope. A holistic study of circulating immune cell responses to different activators is lacking.

The lethal sex gap: COVID-19.

While Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is disrupting lives across the globe for everyone, it has a more devastating impact on the health of older adults, especially that of older men. This pandemic has highlighted the crucial importance of considering an individual's age and biological sex in the clinic in addition to other confounding diseases (Kuchel, G.A, J Am Geriatr Soc, 67, 203, 2019, Tannenbaum, C.

Sestrins induce natural killer function in senescent-like CD8 T cells.

Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8 T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27CD28CD8 T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands.

V-SVA: an R Shiny application for detecting and annotating hidden sources of variation in single-cell RNA-seq data.

Summary: Single-cell RNA-sequencing (scRNA-seq) technology enables studying gene expression programs from individual cells. However, these data are subject to diverse sources of variation, including 'unwanted' variation that needs to be removed in downstream analyses (e.g.

Sexual-dimorphism in human immune system aging.

Differences in immune function and responses contribute to health- and life-span disparities between sexes. However, the role of sex in immune system aging is not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 22-93 years of age using ATAC-seq, RNA-seq, and flow cytometry.

Multiomic Profiling Identifies cis-Regulatory Networks Underlying Human Pancreatic β Cell Identity and Function.

EndoC-βH1 is emerging as a critical human β cell model to study the genetic and environmental etiologies of β cell (dys)function and diabetes. Comprehensive knowledge of its molecular landscape is lacking, yet required, for effective use of this model. Here, we report chromosomal (spectral karyotyping), genetic (genotyping), epigenomic (ChIP-seq and ATAC-seq), chromatin interaction (Hi-C and Pol2 ChIA-PET), and transcriptomic (RNA-seq and miRNA-seq) maps of EndoC-βH1.

Cell Specificity of Human Regulatory Annotations and Their Genetic Effects on Gene Expression.

Epigenomic signatures from histone marks and transcription factor (TF)-binding sites have been used to annotate putative gene regulatory regions. However, a direct comparison of these diverse annotations is missing, and it is unclear how genetic variation within these annotations affects gene expression. Here, we compare five widely used annotations of active regulatory elements that represent high densities of one or more relevant epigenomic marks-"super" and "typical" (nonsuper) enhancers, stretch enhancers, high-occupancy target (HOT) regions, and broad domains-across the four matched human cell types for which they are available.

A CD4 T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate.

Understanding the mechanisms underlying autoantibody development will accelerate therapeutic target identification in autoimmune diseases such as systemic lupus erythematosus (SLE). Follicular helper T cells (T cells) have long been implicated in SLE pathogenesis. Yet a fraction of autoantibodies in individuals with SLE are unmutated, supporting that autoreactive B cells also differentiate outside germinal centers.

Detection of correlated hidden factors from single cell transcriptomes using Iteratively Adjusted-SVA (IA-SVA).

Single cell RNA-sequencing (scRNA-seq) precisely characterizes gene expression levels and dissects variation in expression associated with the state (technical or biological) and the type of the cell, which is averaged out in bulk measurements. Multiple and correlated sources contribute to gene expression variation in single cells, which makes their estimation difficult with the existing methods developed for batch correction (e.g.