Most spatial epidemiological studies of nature-health relationships use generalized greenspace measures. For instance, coarse-resolution spatial data containing normalized difference vegetative index (NDVI) values are prominent despite criticisms, such as the inability to restrain exposure estimates to public and private land. Non-threatening natural landscapes can improve health by building capacities for health-promoting behaviors. Recreational and accessible parks may best activate such behaviors. We curated the Parks and Protected Areas Database of the U.S. (PAD-US) to identify parks that are accessible for outdoor recreation. Our title adds AR to PAD-US where A = Accessible and R = Recreational. We validated the PAD-US-AR by comparisons with greenspace datasets and sociodemographics, which demonstrated its uniqueness from other commonly employed metrics of nature exposure. The PAD-US-AR presents reliable estimates of parks in the contiguous U.S. that are accessible for outdoor recreation. It has strong associations with home prices, shares of female residents, and shares of older residents. This dataset can accompany other nature exposure metrics in environmental epidemiology and allied research fields.

Understanding colloid transport in porous media under transient-flow conditions is crucial in understanding contaminant transport in soil or the vadose zone where flow conditions vary constantly. In this article, we provide a review of experimental studies, numerical approaches, and new technologies available to determine the transport of colloids in transient flow. Experiments indicate that soil structure and preferential flow are primary factors. In undisturbed soils with preferential flow pathways, macropores serve as main conduits for colloid transport. In homogeneously packed soil, the soil matrix often serves as filter. At the macroscale, transient flow facilitates colloid transport by frequently disturbing the force balance that retains colloids in the soil as indicated by the offset between colloid breakthrough peaks and discharge peaks. At the pore-scale and under saturated condition, straining, and attachment at solid–water interfaces are the main mechanisms for colloid retention. Variably saturated conditions add more complexity, such as immobile water zones, film straining, attachment to air–water interfaces, and air–water–solid contact lines. Filter ripening, size exclusion, ionic strength, and hydrophobicity are identified as the most influential factors. Our review indicates that microscale and continuum-scale models for colloid transport under transient-flow conditions are rare, compared to the numerous steady-state models. The few transient flow models that do exist are highly parameterized and suffer from a lack of a priori information of required pore-scale parameters. However, new techniques are becoming available to measure colloid transport in real-time and in a nondestructive way that might help to better understand transient flow colloid transport. This article is categorized under: Science of Water > Hydrological Processes Science of Water > Water Quality.

The development of modeling technology to adequately simulate water and pesticide movement within the rice paddy environment faces several challenges. These include: (1) adequately representing ponded conditions; (2) the collection/implementation of temporal/spatial pesticide application data at field scales; (3) the integration of various mixed-landuses simulation schemes. Currently available models do not fully consider these challenges and results may not be sufficiently accurate to represent fate and transport of rice pesticides at watershed scales. Therefore, in this study, an integrated simulation system, "RiceWQ-AnnAGNPS", was developed to fully address these challenges and is illustrated in a California watershed with rice farming practices. The integrated system successfully extends field level simulations to watershed scales while considering the impact of mixed landuses on downstream loadings. Moreover, the system maintains the application information at fine spatial scales and handles varying treated paddy areas via the "split and adjust" approach. The new system was evaluated by investigating the fate and transport of thiobencarb residues in the Colusa Basin, California as a case study. Thiobencarb concentrations in both water and sediment phases were accurately captured by the calibrated RiceWQ model at the edge of field. After spatial upscaling, the integrated system successfully reflected both the seasonal pattern of surface runoff and the timing of monthly thiobencarb loadings. Incorporating future enhancements can further improve model performance by including more detailed water drainage schedules and management practices, improving the accuracy of summer runoff estimations, and incorporating a more sophisticated in-stream process module. This integrated system provides a framework for evaluating rice pesticide impacts as part of a basin level management approach to improve water quality, which can be extended to other rice agrochemicals, or other areas with fine-scale spatial information of pesticide applications.

The functional engagement between an enhancer and its target promoter ensures precise gene transcription¹. Understanding the basis of promoter choice by enhancers has important implications for health and disease. Here we report that functional loss of a preferred promoter can release its partner enhancer to loop to and activate an alternative promoter (or alternative promoters) in the neighbourhood. We refer to this target-switching process as 'enhancer release and retargeting'. Genetic deletion, motif perturbation or mutation, and dCas9-mediated CTCF tethering reveal that promoter choice by an enhancer can be determined by the binding of CTCF at promoters, in a cohesin-dependent manner-consistent with a model of 'enhancer scanning' inside the contact domain. Promoter-associated CTCF shows a lower affinity than that at chromatin domain boundaries and often lacks a preferred motif orientation or a partnering CTCF at the cognate enhancer, suggesting properties distinct from boundary CTCF. Analyses of cancer mutations, data from the GTEx project and risk loci from genome-wide association studies, together with a focused CRISPR interference screen, reveal that enhancer release and retargeting represents an overlooked mechanism that underlies the activation of disease-susceptibility genes, as exemplified by a risk locus for Parkinson's disease (NUCKS1-RAB7L1) and three loci associated with cancer (CLPTM1L-TERT, ZCCHC7-PAX5 and PVT1-MYC).

Background & aims

How benign liver steatosis progresses to nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC) remains elusive. NASH progression entails diverse pathogenic mechanisms and relies on complex cross-talk between multiple tissues such as the gut, adipose tissues, liver, and the brain. Using a hyperphagic mouse fed with a Western diet (WD), we aimed to elucidate the cross-talk and kinetics of hepatic and extrahepatic alterations during NASH-HCC progression, as well as regression.

Methods

Hyperphagic mice lacking a functional Alms1 gene (Foz/Foz) and wild-type littermates were fed WD or standard chow for 12 weeks for NASH/fibrosis and for 24 weeks for HCC development. NASH regression was modeled by switching back to normal chow after NASH development.

Results

Foz+WD mice were steatotic within 1 to 2 weeks, developed NASH by 4 weeks, and grade 3 fibrosis by 12 weeks, accompanied by chronic kidney injury. Foz+WD mice that continued on WD progressed to cirrhosis and HCC within 24 weeks and had reduced survival as a result of cardiac dysfunction. However, NASH mice that were switched to normal chow showed NASH regression, improved survival, and did not develop HCC. Transcriptomic and histologic analyses of Foz/Foz NASH liver showed strong concordance with human NASH. NASH was preceded by an early disruption of gut barrier, microbial dysbiosis, lipopolysaccharide leakage, and intestinal inflammation. This led to acute-phase liver inflammation in Foz+WD mice, characterized by neutrophil infiltration and increased levels of several chemokines/cytokines. The liver cytokine/chemokine profile evolved as NASH progressed, with subsequent predominance by monocyte recruitment.

Conclusions

The Foz+WD model closely mimics the pathobiology and gene signature of human NASH with fibrosis and subsequent HCC. Foz+WD mice provide a robust and relevant preclinical model of NASH, NASH-associated HCC, chronic kidney injury, and heart failure.

Hypercholesterolemia, the driving force of atherosclerosis, accelerates the expansion and mobilization of hematopoietic stem and progenitor cells (HSPCs). The molecular determinants connecting hypercholesterolemia with hematopoiesis are unclear. Here, we report that a somite-derived prohematopoietic cue, AIBP, orchestrates HSPC emergence from the hemogenic endothelium, a type of specialized endothelium manifesting hematopoietic potential. Mechanistically, AIBP-mediated cholesterol efflux activates endothelial Srebp2, the master transcription factor for cholesterol biosynthesis, which in turn transactivates Notch and promotes HSPC emergence. Srebp2 inhibition impairs hypercholesterolemia-induced HSPC expansion. Srebp2 activation and Notch up-regulation are associated with HSPC expansion in hypercholesterolemic human subjects. Genome-wide chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing (RNA-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) indicate that Srebp2 transregulates Notch pathway genes required for hematopoiesis. Our studies outline an AIBP-regulated Srebp2-dependent paradigm for HSPC emergence in development and HPSC expansion in atherosclerotic cardiovascular disease.