It remains challenging to predict regulatory variants in particular tissues or cell types due to highly context-specific gene regulation. By connecting large-scale epigenomic profiles to expression quantitative trait loci (eQTLs) in a wide range of human tissues/cell types, we identify critical chromatin features that predict variant regulatory potential. We present cepip, a joint likelihood framework, for estimating a variant’s regulatory probability in a context-dependent manner. Our method exhibits significant GWAS signal enrichment and is superior to existing cell type-specific methods. Furthermore, using phenotypically relevant epigenomes to weight the GWAS single-nucleotide polymorphisms, we improve the statistical power of the gene-based association test.

We designed and evaluated an active sampling device, using as analytical targets a family of pesticides purported to contribute to honeybee colony collapse disorder. Simultaneous sampling of bulk water and pore water was accomplished using a low-flow, multi-channel pump to deliver water to an array of solid-phase extraction cartridges. Analytes were separated using either liquid or gas chromatography, and analysis was performed using tandem mass spectrometry (MS/MS). Achieved recoveries of fipronil and degradates in water spiked to nominal concentrations of 0.1, 1, and 10 ng/L ranged from 77 ± 12 to 110 ± 18%. Method detection limits (MDLs) were as low as 0.040–0.8 ng/L. Extraction and quantitation of total fiproles at a wastewater-receiving wetland yielded concentrations in surface water and pore water ranging from 9.9 ± 4.6 to 18.1 ± 4.6 ng/L and 9.1 ± 3.0 to 12.6 ± 2.1 ng/L, respectively. Detected concentrations were statistically indistinguishable from those determined by conventional, more laborious techniques (p > 0.2 for the three most abundant fiproles). Aside from offering time-averaged sampling capabilities for two phases simultaneously with picogram-per-liter MDLs, the novel methodology eliminates the need for water and sediment transport via in situ solid phase extraction.

Two distinct monocyte (Mo)/macrophage (Mp) subsets (Ly6C^low and Ly6C^hi) orchestrate cardiac recovery process following myocardial infarction (MI). Prostaglandin (PG) E₂ is involved in the Mo/Mp-mediated inflammatory response, however, the role of its receptors in Mos/Mps in cardiac healing remains to be determined. Here we show that pharmacological inhibition or gene ablation of the Ep3 receptor in mice suppresses accumulation of Ly6C^low Mos/Mps in infarcted hearts. Ep3 deletion in Mos/Mps markedly attenuates healing after MI by reducing neovascularization in peri-infarct zones. Ep3 deficiency diminishes CX3C chemokine receptor 1 (CX3CR1) expression and vascular endothelial growth factor (VEGF) secretion in Mos/Mps by suppressing TGFβ1 signaling and subsequently inhibits Ly6C^low Mos/Mps migration and angiogenesis. Targeted overexpression of Ep3 receptors in Mos/Mps improves wound healing by enhancing angiogenesis. Thus, the PGE₂/Ep3 axis promotes cardiac healing after MI by activating reparative Ly6C^low Mos/Mps, indicating that Ep3 receptor activation may be a promising therapeutic target for acute MI.

Asteroids provide fundamental clues to the formation and evolution of planetesimals. Collisional models based on the depletion of the primordial main belt of asteroids predict 10–15 craters >400 km should have formed on Ceres, the largest object between Mars and Jupiter, over the last 4.55 Gyr. Likewise, an extrapolation from the asteroid Vesta would require at least 6–7 such basins. However, Ceres’ surface appears devoid of impact craters >∼280 km. Here, we show a significant depletion of cerean craters down to 100–150 km in diameter. The overall scarcity of recognizable large craters is incompatible with collisional models, even in the case of a late implantation of Ceres in the main belt, a possibility raised by the presence of ammoniated phyllosilicates. Our results indicate that a significant population of large craters has been obliterated, implying that long-wavelength topography viscously relaxed or that Ceres experienced protracted widespread resurfacing.

Accumulating data from genome-wide association studies (GWAS) have provided a collection of novel candidate genes associated with complex diseases, such as atherosclerosis. We identified an atherosclerosis-associated single-nucleotide polymorphism (SNP) located in the intron of the long noncoding RNA (lncRNA) LINC00305 by searching the GWAS database. Although the function of LINC00305 is unknown, we found that LINC00305 expression is enriched in atherosclerotic plaques and monocytes. Overexpression of LINC00305 promoted the expression of inflammation-associated genes in THP-1 cells and reduced the expression of contractile markers in co-cultured human aortic smooth muscle cells (HASMCs). We showed that overexpression of LINC00305 activated nuclear factor-kappa beta (NF-κB) and that inhibition of NF-κB abolished LINC00305-mediated activation of cytokine expression. Mechanistically, LINC00305 interacted with lipocalin-1 interacting membrane receptor (LIMR), enhanced the interaction of LIMR and aryl-hydrocarbon receptor repressor (AHRR), and promoted protein expression as well as nuclear localization of AHRR. Moreover, LINC00305 activated NF-κB exclusively in the presence of LIMR and AHRR. In light of these findings, we propose that LINC00305 promotes monocyte inflammation by facilitating LIMR and AHRR cooperation and the AHRR activation, which eventually activates NF-κB, thereby inducing HASMC phenotype switching.

Despite increasing interest in the effects of triclosan and triclocarban on human biology, current knowledge is still limited on the impact of these additives to antimicrobial personal care products on the human microbiome. A carefully designed recent study published in mSphere by Poole and colleagues [A. C. Poole et al., mSphere 1(3):e00056-15, 2016, http://dx.doi.org/10.1128/mSphere.00056-15] highlights both the power of novel methodologies for microbiome elucidation and the longstanding challenge of employing small-cohort studies to inform risk assessment for chemicals of ubiquitous use in modern society.

Traditionally, hazardous chemicals have been regulated in the U.S. on a one-by-one basis, an approach that is slow, expensive and can be inefficient, as illustrated by a decades-long succession of replacing one type of organohalogen flame retardants (OHFRs) with another one, without addressing the root cause of toxicity and associated public health threats posed. The present article expounds on the need for efficient monitoring strategies and pragmatic steps in reducing environmental pollution and adverse human health impacts. A promising approach is to combine specific bioassays with state-of-the-art chemical screening to identify chemicals and chemical mixtures sharing specific modes of action (MOAs) and pathways of toxicity (PoTs). This approach could be used to identify and regulate hazardous chemicals as classes or compound families, featuring similar biological end-points, such as endocrine disruption and mutagenicity. Opportunities and potential obstacles of implementing this approach are discussed.

Processed municipal sewage sludges (MSS) are an abundant, unwanted by-product of wastewater treatment, increasingly applied to agriculture and forestry for inexpensive disposal and soil conditioning. Due to their high organic carbon and lipid contents, MSS not only is rich in carbon and nutrients but also represents a “sink” for recalcitrant, hydrophobic, and potentially bioaccumulative compounds. Indeed, many organics sequestered and concentrated in MSS meet the US Environmental Protection Agency’s definition of being persistent, bioaccumulative, and toxic (PBT). In a strategic effort, our research team at the Biodesign Institute has created the National Sewage Sludge Repository (NSSR), a large repository of digested MSSs from 164 wastewater treatment plants from across the USA, as part of the Human Health Observatory (H2O) at Arizona State University (ASU). The NSSR likely represents the largest archive of digested MSS specimens in the USA. The present study summarizes key findings gleaned thus far from analysis of NSSR samples. For example, we evaluated the content of toxicants in MSS and computed estimates of nationwide inventories of mass produced chemicals that become sequestrated in sludge and later are released into the environment during sludge disposal on land. Ongoing efforts document co-occurrence of a variety of PBT compounds in both MSS and human samples, while also identifying a large number of potentially harmful MSS constituents for which human exposure data are still lacking. Finally, we summarize future opportunities and invite collaborative use of the NSSR by the research community. The H2O at ASU represents a new resource and research tool for environmental scientists and the larger research community. As illustrated in this work, this repository can serve to (i) identify and prioritize emerging contaminants, (ii) provide spatial and temporal trends of contaminants, (iii) inform and evaluate the effectiveness of environmental policy-making and regulations, and (iv) approximate, ongoing exposures and body burdens of mass-produced chemicals in human society.

The known occurrence of pharmaceuticals in the built and natural water environment, including in drinking water supplies, continues to raise concerns over inadvertent exposures and associated potential health risks in humans and aquatic organisms. At the same time, the number and concentrations of new and existing pharmaceuticals in the water environment are destined to increase further in the future as a result of increased consumption of pharmaceuticals by a growing and aging population and ongoing measures to decrease per-capita water consumption. This review examines the occurrence and movement of pharmaceuticals in the built and natural water environment, with special emphasis on contamination of the drinking water supply, and opportunities for sustainable pollution control. We surveyed peer-reviewed publications dealing with quantitative measurements of pharmaceuticals in U.S. drinking water, surface water, groundwater, raw and treated wastewater as well as municipal biosolids. Pharmaceuticals have been observed to reenter the built water environment contained in raw drinking water, and they remain detectable in finished drinking water at concentrations in the ng/L to μg/L range. The greatest promises for minimizing pharmaceutical contamination include source control (for example, inputs from intentional flushing of medications for safe disposal, and sewer overflows), and improving efficiency of treatment facilities.