MicroRNA-directed program of cytotoxic CD8+ T-cell differentiation.

Acquisition of effector properties is a key step in the generation of cytotoxic T lymphocytes (CTLs). Here we show that inflammatory signals regulate Dicer expression in CTLs, and that deletion or depletion of Dicer in mouse or human activated CD8(+) T cells causes up-regulation of perforin, granzymes, and effector cytokines. Genome-wide analysis of microRNA (miR, miRNA) changes induced by exposure of differentiating CTLs to IL-2 and inflammatory signals identifies miR-139 and miR-150 as components of an miRNA network that controls perforin, eomesodermin, and IL-2Rα expression in differentiating CTLs and whose activity is modulated by IL-2, inflammation, and antigenic stimulation. Overall, our data show that strong IL-2R and inflammatory signals act through Dicer and miRNAs to control the cytolytic program and other aspects of effector CTL differentiation.

Wildfire smoke exposure and human health: Significant gaps in research for a growing public health issue.

Understanding the effect of wildfire smoke exposure on human health represents a unique interdisciplinary challenge to the scientific community. Population health studies indicate that wildfire smoke is a risk to human health and increases the healthcare burden of smoke-impacted areas. However, wildfire smoke composition is complex and dynamic, making characterization and modeling difficult. Furthermore, current efforts to study the effect of wildfire smoke are limited by availability of air quality measures and inconsistent air quality reporting among researchers. To help address these issues, we conducted a substantive review of wildfire smoke effects on population health, wildfire smoke exposure in occupational health, and experimental wood smoke exposure. Our goal was to evaluate the current literature on wildfire smoke and highlight important gaps in research. In particular we emphasize long-term health effects of wildfire smoke, recovery following wildfire smoke exposure, and health consequences of exposure in children.

Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex.

ASXL1 is the obligate regulatory subunit of a deubiquitinase complex whose catalytic subunit is BAP1. Heterozygous mutations of ASXL1 that result in premature truncations are frequent in myeloid leukemias and Bohring-Opitz syndrome. Here we demonstrate that ASXL1 truncations confer enhanced activity on the ASXL1-BAP1 complex. Stable expression of truncated, hyperactive ASXL1-BAP1 complexes in a haematopoietic precursor cell line results in global erasure of H2AK119Ub, striking depletion of H3K27me3, selective upregulation of a subset of genes whose promoters are marked by both H2AK119Ub and H3K4me3, and spontaneous differentiation to the mast cell lineage. These outcomes require the catalytic activity of BAP1, indicating that they are downstream consequences of H2AK119Ub erasure. In bone marrow precursors, expression of truncated ASXL1-BAP1 complex cooperates with TET2 loss-of-function to increase differentiation to the myeloid lineage in vivo. Our data raise the possibility that ASXL1 truncation mutations confer gain-of-function on the ASXL-BAP1 complex.