Variability of the innate immune response is globally constrained by transcriptional bursting.

Transcription of almost all mammalian genes occurs in stochastic bursts, however the fundamental control mechanisms that allow appropriate single-cell responses remain unresolved. Here we utilise single cell genomics data and stochastic models of transcription to perform global analysis of the toll-like receptor (TLR)-induced gene expression variability. Based on analysis of more than 2000 TLR-response genes across multiple experimental conditions we demonstrate that the single-cell, gene-by-gene expression variability can be empirically described by a linear function of the population mean. We show that response heterogeneity of individual genes can be characterised by the slope of the mean-variance line, which captures how cells respond to stimulus and provides insight into evolutionary differences between species. We further demonstrate that linear relationships theoretically determine the underlying transcriptional bursting kinetics, revealing different regulatory modes of TLR response heterogeneity. Stochastic modelling of temporal scRNA-seq count distributions demonstrates that increased response variability is associated with larger and more frequent transcriptional bursts, which emerge via increased complexity of transcriptional regulatory networks between genes and different species. Overall, we provide a methodology relying on inference of empirical mean-variance relationships from single cell data and new insights into control of innate immune response variability.

A baseline of copper associated with antifouling paint in marinas within a large fjord estuary.

Marinas have been shown to contribute elevated concentrations of copper (Cu) to marine waters. The Cu can come primarily from antifouling paints which are designed to discourage biofouling of boat hulls. Legislation in Washington State, USA is being developed to limit or regulate the amount and rate of diffusion of Cu from antifouling paints. This study provides baseline data for Cu in five marinas of different configuration and size within Puget Sound, a large fjord estuary. Samples were collected over a year from multiple environmental media. We find strong evidence that Cu accumulates inside marinas to higher concentrations than outside marinas. Marinas that are more enclosed accumulated higher concentrations of Cu than more open marinas. Using a power analysis, we assessed the adequacy of the baseline dataset to measure progress as a result of future legislation towards the reduction of Cu to Puget Sound from marinas.

In situ biomonitoring of PAH-contaminated sediments using juvenile coho salmon (Oncorhynchus kisutch).

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous marine and freshwater sediment contaminants. Extensive data exist to confirm that PAHs are toxic to aquatic receptors. However, limited information is available regarding the bioavailability and genotoxicity of sediment PAHs to aquatic organisms. This study investigated an integrated biomonitoring approach using chemical analyses and biomarkers to characterize the bioavailability and genotoxicity of a complex PAH mixture in freshwater lake sediments associated with a former manufactured gas plant (MGP). Sediment PAH genotoxicity was assessed by flow cytometry (FCM), DNA adduct (32)P-postlabeling, and erythrocyte micronuclei in juvenile coho salmon (Oncorhynchus kisutch) caged in the water column. Significant PAH-induced genotoxicity was observed with FCM and (32)P-postlabeling, but not with erythrocyte micronuclei. Chromosome damage in peripheral blood and hepatic DNA adducts correlated with sediment, but not water column PAH concentrations. Total hepatic DNA adducts in salmon caged nearest the former MGP facility was 39+/-6.5 (RALx10(9)), while salmon caged in a reference lake had 28+/-2.3 total hepatic DNA adducts per 10(9) nucleotides. These results indicate that in situ biomonitoring using biomarkers and caged fish can be a sensitive indicator of genotoxic PAHs in sediments.