Relation of CMV and brain atrophy to trajectories of immunosenescence in diverse populations.

Immunosenescence (ISC), the aging of the immune system, has largely been studied in populations of European descent. Here, circulating immune cell cytometric data from African-American, Hispanic, and non-Hispanic White participants were generated. Known and novel age effects were identified using either a meta-analysis approach or a parallel genetic approach.

HDAC Inhibitors recapitulate Human Disease-Associated Microglia Signatures .

Disease-associated microglia (DAM), initially described in mouse models of neurodegenerative diseases, have been classified into two related states; starting from a TREM2-independent DAM1 state to a TREM2 dependent state termed DAM2, with each state being characterized by the expression of specific marker genes. Recently, single-cell (sc)RNA-Seq studies have reported the existence of DAMs in humans; however, whether DAMs play beneficial or detrimental roles in the context of neurodegeneration is still under debate. Here, we present a pharmacological approach to mimic human DAM by exposing different human microglia models to selected histone deacetylase (HDAC) inhibitors.

A pharmacological toolkit for human microglia identifies Topoisomerase I inhibitors as immunomodulators for Alzheimer's disease.

While efforts to identify microglial subtypes have recently accelerated, the relation of transcriptomically defined states to function has been largely limited to annotations. Here, we characterize a set of pharmacological compounds that have been proposed to polarize human microglia towards two distinct states - one enriched for AD and MS genes and another characterized by increased expression of antigen presentation genes. Using different model systems including HMC3 cells, iPSC-derived microglia and cerebral organoids, we characterize the effect of these compounds in mimicking human microglial subtypes .

AP-1 transcription factor network explains diverse patterns of cellular plasticity in melanoma cells.

Cellular plasticity associated with fluctuations in transcriptional programs allows individual cells in a tumor to adopt heterogeneous differentiation states and switch phenotype during their adaptive responses to therapies. Despite increasing knowledge of such transcriptional programs, the molecular basis of cellular plasticity remains poorly understood. Here, we combine multiplexed transcriptional and protein measurements at population and single-cell levels with multivariate statistical modeling to show that the state of AP-1 transcription factor network plays a unifying role in explaining diverse patterns of plasticity in melanoma.

Phenotype-based probabilistic analysis of heterogeneous responses to cancer drugs and their combination efficacy.

Cell-to-cell variability generates subpopulations of drug-tolerant cells that diminish the efficacy of cancer drugs. Efficacious combination therapies are thus needed to block drug-tolerant cells via minimizing the impact of heterogeneity. Probabilistic models such as Bliss independence have been developed to evaluate drug interactions and their combination efficacy based on probabilities of specific actions mediated by drugs individually and in combination.

Role of heterogeneous cell population on modulation of dendritic cell phenotype and activation of CD8 T cells for use in cell-based immunotherapies.

Dendritic cell (DC)-based immunotherapies have much utility in their ability to prime antigen-specific adaptive immune responses. However, there does not yet exist a consensus standard to how DCs should be primed. In this study, we aimed to determine the role of heterogeneous co-cultures, composed of both CD11c+ (DCs) and CD11c- cells, in combination with monophosphoryl lipid A (MPLA) stimulation on DC phenotype and function.