Knowledge of cell type composition in disease relevant tissues is an important step towards the identification of cellular targets of disease. We present MuSiC, a method that utilizes cell-type ...specific gene expression from single-cell RNA sequencing (RNA-seq) data to characterize cell type compositions from bulk RNA-seq data in complex tissues. By appropriate weighting of genes showing cross-subject and cross-cell consistency, MuSiC enables the transfer of cell type-specific gene expression information from one dataset to another. When applied to pancreatic islet and whole kidney expression data in human, mouse, and rats, MuSiC outperformed existing methods, especially for tissues with closely related cell types. MuSiC enables the characterization of cellular heterogeneity of complex tissues for understanding of disease mechanisms. As bulk tissue data are more easily accessible than single-cell RNA-seq, MuSiC allows the utilization of the vast amounts of disease relevant bulk tissue RNA-seq data for elucidating cell type contributions in disease.
Our understanding of kidney disease pathogenesis is limited by an incomplete molecular characterization of the cell types responsible for the organ's multiple homeostatic functions. To help fill this ...knowledge gap, we characterized 57,979 cells from healthy mouse kidneys by using unbiased single-cell RNA sequencing. On the basis of gene expression patterns, we infer that inherited kidney diseases that arise from distinct genetic mutations but share the same phenotypic manifestation originate from the same differentiated cell type. We also found that the collecting duct in kidneys of adult mice generates a spectrum of cell types through a newly identified transitional cell. Computational cell trajectory analysis and in vivo lineage tracing revealed that intercalated cells and principal cells undergo transitions mediated by the Notch signaling pathway. In mouse and human kidney disease, these transitions were shifted toward a principal cell fate and were associated with metabolic acidosis.
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BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Chronic inflammation is postulated to be involved in the development of end-stage renal disease in diabetes, but which specific circulating inflammatory proteins contribute to this risk remain ...unknown. To study this, we examined 194 circulating inflammatory proteins in subjects from three independent cohorts with type 1 and type 2 diabetes. In each cohort, we identified an extremely robust kidney risk inflammatory signature (KRIS), consisting of 17 proteins enriched in tumor necrosis factor-receptor superfamily members, that was associated with a 10-year risk of end-stage renal disease. All these proteins had a systemic, non-kidney source. Our prospective study findings provide strong evidence that KRIS proteins contribute to the inflammatory process underlying end-stage renal disease development in both types of diabetes. These proteins point to new therapeutic targets and new prognostic tests to identify subjects at risk of end-stage renal disease, as well as biomarkers to measure responses to treatment of diabetic kidney disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Fibrosis is the final common pathway leading to end-stage renal failure. By analyzing the kidneys of patients and animal models with fibrosis, we observed a significant mitochondrial defect, ...including the loss of the mitochondrial transcription factor A (TFAM) in kidney tubule cells. Here, we generated mice with tubule-specific deletion of TFAM (Ksp-Cre/Tfam
). While these mice developed severe mitochondrial loss and energetic deficit by 6 weeks of age, kidney fibrosis, immune cell infiltration, and progressive azotemia causing death were only observed around 12 weeks of age. In renal cells of TFAM KO (knockout) mice, aberrant packaging of the mitochondrial DNA (mtDNA) resulted in its cytosolic translocation, activation of the cytosolic cGAS-stimulator of interferon genes (STING) DNA sensing pathway, and thus cytokine expression and immune cell recruitment. Ablation of STING ameliorated kidney fibrosis in mouse models of chronic kidney disease, demonstrating how TFAM sequesters mtDNA to limit the inflammation leading to fibrosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Bone marrow mesenchymal lineage cells are a heterogeneous cell population involved in bone homeostasis and diseases such as osteoporosis. While it is long postulated that they originate from ...mesenchymal stem cells, the true identity of progenitors and their in vivo bifurcated differentiation routes into osteoblasts and adipocytes remain poorly understood. Here, by employing large scale single cell transcriptome analysis, we computationally defined mesenchymal progenitors at different stages and delineated their bi-lineage differentiation paths in young, adult and aging mice. One identified subpopulation is a unique cell type that expresses adipocyte markers but contains no lipid droplets. As non-proliferative precursors for adipocytes, they exist abundantly as pericytes and stromal cells that form a ubiquitous 3D network inside the marrow cavity. Functionally they play critical roles in maintaining marrow vasculature and suppressing bone formation. Therefore, we name them marrow adipogenic lineage precursors (MALPs) and conclude that they are a newly identified component of marrow adipose tissue.
Epigenetic changes might provide the biological explanation for the long-lasting impact of metabolic alterations of diabetic kidney disease development. Here we examined cytosine methylation of human ...kidney tubules using Illumina Infinium 450 K arrays from 91 subjects with and without diabetes and varying degrees of kidney disease using a cross-sectional design. We identify cytosine methylation changes associated with kidney structural damage and build a model for kidney function decline. We find that the methylation levels of 65 probes are associated with the degree of kidney fibrosis at genome wide significance. In total 471 probes improve the model for kidney function decline. Methylation probes associated with kidney damage and functional decline enrich on kidney regulatory regions and associate with gene expression changes, including epidermal growth factor (EGF). Altogether, our work shows that kidney methylation differences can be detected in patients with diabetic kidney disease and improve kidney function decline models indicating that they are potentially functionally important.
The prevalence of genital human papillomavirus (HPV) in women with endometriosis has never been reported in a national representative survey. We aimed to investigate the association of endometriosis ...with the prevalence of HPV. We analyzed the data on 1768 women (representing 43,824,157 women) in the United States aged 20-54 years from the National Health and Nutrition Examination Survey in the prevaccination era (2003-2006). The diagnosis of endometriosis was based on a self-report. The prevalence of any HPV in women with endometriosis did not differ from that in women without endometriosis after controlling for potential confounders such as age, ethnicity, family income, marital status, and the number of deliveries (adjusted prevalence ratio (aPR) 0.84, 95% confidence interval (CI) 0.61-1.15). No significant association was found between the prevalence of high-risk HPV and the diagnosis of endometriosis (aPR 0.71, 95% CI 0.44-1.14). If the participants were not covered by health insurance, the prevalence of any HPV infection in women with endometriosis was higher than in those without endometriosis (aPR 1.44, 95% CI 0.94-2.20). In contrast, in a subgroup who had health insurance, a lower prevalence of any HPV infection was observed in women with endometriosis (aPR 0.71, 95% CI 0.50-1.03), and P for interaction was statistically significant (P = 0.01). There was no association between endometriosis and HPV infection in this study of HPV vaccine-naïve women of reproductive age. The association was not different by the type of HPV. However, access to healthcare may modify the association between endometriosis and HPV infection.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The freeze–thaw action of water inside rocks’ pores, cracks, and joints plays a dominant role in physical rock weathering where the temperature fluctuates across 0 °C. To understand this process in ...cold regions, artificial weathering was simulated in the laboratory. Diorite, basalt, and tuff were used as specimen, and were maintained in saturated conditions to accelerate the effect of freeze–thaw weathering. X-ray computed tomography (CT) images and scanning electron microscope (SEM) photographs were obtained to investigate changes in the inner microstructure along with repeated freeze–thaw cycles. In addition, physical properties were measured during the cycles. Particle detachment, crack initiation, and propagation and porosity increase due to volumetric expansion of water inside rocks were detected using X-ray CT and SEM. The decrease in P-wave and S-wave velocities, and in weight loss were also observed. Tuff specimens, which have low tensile strength, high porosity, and loose structure, were deteriorated rapidly, while diorite specimens on the other hand, which have high tensile strength, low porosity, and compact structure, showed relatively slight changes. The frost susceptibility of basalt specimens was found to be intermediate between tuff and diorite. The developed process for cycling and freezing set up can be useful to test the various stones in terms of frost susceptibility.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cancer-associated fibroblasts (CAFs) are the predominant components of the tumor microenvironment (TME) and influence cancer hallmarks, but without systematic investigation on their ubiquitous ...characteristics across different cancer types. Here, we perform pan-cancer analysis on 226 samples across 10 solid cancer types to profile the TME at single-cell resolution, illustrating the commonalities/plasticity of heterogenous CAFs. Activation trajectory of the major CAF types is divided into three states, exhibiting distinct interactions with other cell components, and relating to prognosis of immunotherapy. Moreover, minor CAF components represent the alternative origin from other TME components (e.g., endothelia and macrophages). Particularly, the ubiquitous presentation of endothelial-to-mesenchymal transition CAF, which may interact with proximal SPP1
tumor-associated macrophages, is implicated in endothelial-to-mesenchymal transition and survival stratifications. Our study comprehensively profiles the shared characteristics and dynamics of CAFs, and highlight their heterogeneity and plasticity across different cancer types. Browser of integrated pan-cancer single-cell information is available at https://gist-fgl.github.io/sc-caf-atlas/ .
This paper reviews state-of-the-art dielectric elastomer actuators (DEAs) and their future perspectives as soft actuators which have recently been considered as a key power generation component for ...soft robots. This paper begins with the introduction of the working principle of the dielectric elastomer actuators. Because the operation of DEA includes the physics of both mechanical viscoelastic properties and dielectric characteristics, we describe theoretical modeling methods for the DEA before introducing applications. In addition, the design of artificial muscles based on DEA is also introduced. This paper reviews four popular subjects for the application of DEA: soft robot hand, locomotion robots, wearable devices, and tunable optical components. Other potential applications and challenging issues are described in the conclusion.
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