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The glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) have distinct, yet overlapping physiological and pathophysiological functions. There are indications that both receptors interact functionally and physically, but the precise role of this interdependence is poorly understood. Here, we analyzed the impact of GR coexpression on MR genome-wide transcriptional responses and chromatin binding upon activation by aldosterone and glucocorticoids, both physiological ligands of this receptor. Transcriptional responses of MR in the absence of GR result in fewer regulated genes. In contrast, coexpression of GR potentiates MR-mediated transcription, particularly in response to aldosterone, both in cell lines and in the more physiologically relevant model of mouse colon organoids. MR chromatin binding is altered by GR coexpression in a locus- and ligand-specific way. Single-molecule tracking of MR suggests that the presence of GR contributes to productive binding of MR/aldosterone complexes to chromatin. Together, our data indicate that coexpression of GR potentiates aldosterone-mediated MR transcriptional activity, even in the absence of glucocorticoids. 

ABSTRACT The OpenStreetMap (OSM) project allows volunteers in the community to contribute and manage spatial data collaboratively and provides free spatial data with global coverage to the public. OSM data have been widely used in many applications. However, the quality of OSM data can be inconsistent due to the crowdsourcing nature of the OSM project. This study compares the OSM road data with the national road data from the U.S. Census Topologically Integrated Geographic Encoding and Referencing system (TIGER) project in the contiguous United States. Specifically, we used three indicators to examine the completeness and positional accuracy of the OSM road data at the county level. Then we performed spatial analysis to study the patterns of the discrepancies. Our results show that OSM road data are inconsistent in completeness and positional accuracy across different counties. Finally, we compared the three indicators among metropolitan, nonmetropolitan, and rural counties with Analysis of Variance (ANOVA) and Boxplot. The results show that the OSM road data in metropolitan counties have better completeness and positional accuracy than those in nonmetropolitan and rural counties. This study can improve our understanding of the quality of OSM road data in the United States, which in turn can help the OSM community improve the quality of road data and allow data users to better use OSM road data in different applications. 

Abstract To understand phenotypic variations and key factors which affect disease susceptibility of complex traits, it is important to decipher cell‐type tissue compositions. To study cellular compositions of bulk tissue samples, one can evaluate cellular abundances and cell‐type‐specific gene expression patterns from the tissue transcriptome profiles. We develop both fixed and mixed models to reconstruct cellular expression fractions for bulk‐profiled samples by using reference single‐cell (sc) RNA‐sequencing (RNA‐seq) reference data. In benchmark evaluations of estimating cellular expression fractions, the mixed‐effect models provide similar results as an elegant machine learning algorithm named cell‐type identification by estimating relative subsets of RNA transcripts (CIBERSORTx), which is a well‐known and reliable procedure to reconstruct cell‐type abundances and cell‐type‐specific gene expression profiles. In real data analysis, the mixed‐effect models outperform or perform similarly as CIBERSORTx. The mixed models perform better than the fixed models in both benchmark evaluations and data analysis. In simulation studies, we show that if the heterogeneity exists in scRNA‐seq data, it is better to use mixed models with heterogeneous mean and variance–covariance. As a byproduct, the mixed models provide fractions of covariance between subject‐specific gene expression and cell types to measure their correlations. The proposed mixed models provide a complementary tool to dissect bulk tissues using scRNA‐seq data. 

Significance Tumor progression to enable metastasis includes remodeling the wavy bundles of collagen making up the tissue stromal extracellular matrix (ECM) into straight bundles within the tumor microenvironment. While wavy collagen bundles are thought to be inhibitory to cell polarization and migration in tissue, straight ECM fibers are thought to be conducive, thereby mediating metastasis. We used nanofabricated cell culture substrates that mimic the ECM fiber waveforms seen in both benign- and metastases-promoting tumor ECMs. Large amplitude ECM waves depolarized tumor cells and decreased directional migration via cell contractility-mediated organization of the cytoskeleton and adhesions. Thus, ECM architecture of normal tissue and benign tumors may generally inhibit tumor cell exit, but this may be overcome by increasing tumor cell contractility. 

ABSTRACT Age‐related skeletal muscle atrophy, known as sarcopenia, is characterized by loss of muscle mass, strength, endurance, and oxidative capacity. Although exercise has been shown to mitigate sarcopenia, the underlying governing mechanisms are poorly understood. Mitochondrial dysfunction is implicated in aging and sarcopenia; however, few studies explore how mitochondrial structure contributes to this dysfunction. In this study, we sought to understand how aging impacts mitochondrial three‐dimensional (3D) structure and its regulators in skeletal muscle. We hypothesized that aging leads to remodeling of mitochondrial 3D architecture permissive to dysfunction and is ameliorated by exercise. Using serial block‐face scanning electron microscopy (SBF‐SEM) and Amira software, mitochondrial 3D reconstructions from patient biopsies were generated and analyzed. Across five human cohorts, we correlate differences in magnetic resonance imaging, mitochondria 3D structure, exercise parameters, and plasma immune markers between young (under 50 years) and old (over 50 years) individuals. We found that mitochondria are less spherical and more complex, indicating age‐related declines in contact site capacity. Additionally, aged samples showed a larger volume phenotype in both female and male humans, indicating potential mitochondrial swelling. Concomitantly, muscle area, exercise capacity, and mitochondrial dynamic proteins showed age‐related losses. Exercise stimulation restored mitofusin 2 (MFN2), one such of these mitochondrial dynamic proteins, which we show is required for the integrity of mitochondrial structure. Furthermore, we show that this pathway is evolutionarily conserved, as Marf, the MFN2 ortholog inDrosophila, knockdown alters mitochondrial morphology and leads to the downregulation of genes regulating mitochondrial processes. Our results define age‐related structural changes in mitochondria and further suggest that exercise may mitigate age‐related structural decline through modulation of mitofusin 2. 

Abstract We present time‐resolved Gd−Gd electron paramagnetic resonance (TiGGER) at 240 GHz for tracking inter‐residue distances during a protein's mechanical cycle in the solution state. TiGGER makes use of Gd‐sTPATCN spin labels, whose favorable qualities include a spin‐7/2 EPR‐active center, short linker, narrow intrinsic linewidth, and virtually no anisotropy at high fields (8.6 T) when compared to nitroxide spin labels. Using TiGGER, we determined that upon light activation, the C‐terminus and N‐terminus of AsLOV2 separate in less than 1 s and relax back to equilibrium with a time constant of approximately 60 s. TiGGER revealed that the light‐activated long‐range mechanical motion is slowed in the Q513A variant of AsLOV2 and is correlated to the similarly slowed relaxation of the optically excited chromophore as described in recent literature. TiGGER has the potential to valuably complement existing methods for the study of triggered functional dynamics in proteins. 

Abstract Near‐infrared (NIR) fluorescent dyes with favorable photophysical properties are highly useful for bioimaging, but such dyes are still rare. The development of a unique class of NIR dyes via modifying the rhodol scaffold with fused tetrahydroquinoxaline rings is described. These new dyes showed large Stokes shifts (>110 nm). Among them, WR3, WR4, WR5, and WR6 displayed high fluorescence quantum yields and excellent photostability in aqueous solutions. Moreover, their fluorescence properties were tunable by easy modifications on the phenolic hydroxy group. Based on WR6, two NIR fluorescent turn‐on probes, WSP‐NIR and SeSP‐NIR, were devised for the detection of H₂S. The probe SeSP‐NIR was applied in visualizing intracellular H₂S. These dyes are expected to be useful fluorophore scaffolds in the development of new NIR probes for bioimaging.