Mechanisms of Renal Fibrosis Humphreys, Benjamin D
Annual review of physiology,
02/2018, Letnik:
80, Številka:
1
Journal Article
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Tubulointerstitial fibrosis is a chronic and progressive process affecting kidneys during aging and in chronic kidney disease (CKD), regardless of cause. CKD and renal fibrosis affect half of adults ...above age 70 and 10% of the world's population. Although no targeted therapy yet exists to slow renal fibrosis, a number of important recent advances have clarified the cellular and molecular mechanisms underlying the disease. In this review, I highlight these advances with a focus on cells and pathways that may be amenable to therapeutic targeting. I discuss pathologic changes regulating interstitial myofibroblast activation, including profibrotic and proinflammatory paracrine signals secreted by epithelial cells after either acute or chronic injury. I conclude by highlighting novel therapeutic targets and approaches with particular promise for development of new treatments for patients with fibrotic kidney disease.
In adult tissues, an exquisite balance exists between stem cell proliferation and the generation of differentiated offspring. Classically, it has been argued that this balance is obtained at the ...level of a single stem cell, which divides strictly into a new stem cell and a progenitor. However, recent evidence suggests that balance can also be achieved at the level of the stem cell population. Some stem cells might be lost due to differentiation or damage, whereas others divide symmetrically to fill this gap. Here, we consider the general strategies for stem cell self-renewal and review the evidence for stochastic stem cell fate in adult tissues across a range of tissue types and organisms.
With the proliferation of online data collection in human-subjects research, concerns have been raised over the presence of inattentive survey participants and non-human respondents (bots). We ...compared the quality of the data collected through five commonly used platforms. Data quality was indicated by the percentage of participants who meaningfully respond to the researcher's question (high quality) versus those who only contribute noise (low quality). We found that compared to MTurk, Qualtrics, or an undergraduate student sample (i.e., SONA), participants on Prolific and CloudResearch were more likely to pass various attention checks, provide meaningful answers, follow instructions, remember previously presented information, have a unique IP address and geolocation, and work slowly enough to be able to read all the items. We divided the samples into high- and low-quality respondents and computed the cost we paid per high-quality respondent. Prolific ($1.90) and CloudResearch ($2.00) were cheaper than MTurk ($4.36) and Qualtrics ($8.17). SONA cost $0.00, yet took the longest to collect the data.
Nucleotide sequence and taxonomy reference databases are critical resources for widespread applications including marker-gene and metagenome sequencing for microbiome analysis, diet metabarcoding, ...and environmental DNA (eDNA) surveys. Reproducibly generating, managing, using, and evaluating nucleotide sequence and taxonomy reference databases creates a significant bottleneck for researchers aiming to generate custom sequence databases. Furthermore, database composition drastically influences results, and lack of standardization limits cross-study comparisons. To address these challenges, we developed RESCRIPt, a Python 3 software package and QIIME 2 plugin for reproducible generation and management of reference sequence taxonomy databases, including dedicated functions that streamline creating databases from popular sources, and functions for evaluating, comparing, and interactively exploring qualitative and quantitative characteristics across reference databases. To highlight the breadth and capabilities of RESCRIPt, we provide several examples for working with popular databases for microbiome profiling (SILVA, Greengenes, NCBI-RefSeq, GTDB), eDNA and diet metabarcoding surveys (BOLD, GenBank), as well as for genome comparison. We show that bigger is not always better, and reference databases with standardized taxonomies and those that focus on type strains have quantitative advantages, though may not be appropriate for all use cases. Most databases appear to benefit from some curation (quality filtering), though sequence clustering appears detrimental to database quality. Finally, we demonstrate the breadth and extensibility of RESCRIPt for reproducible workflows with a comparison of global hepatitis genomes. RESCRIPt provides tools to democratize the process of reference database acquisition and management, enabling researchers to reproducibly and transparently create reference materials for diverse research applications. RESCRIPt is released under a permissive BSD-3 license at https://github.com/bokulich-lab/RESCRIPt.
ABSTRACT
The cross-correlation of gravitational wave strain with upcoming galaxy surveys probes theories of gravity in a new way. This method enables testing the theory of gravity by combining the ...effects from both gravitational lensing of gravitational waves and the propagation of gravitational waves in space–time. We find that within 10 yr the combination of the Advanced LIGO (Laser Interferometer Gravitational-Wave Observatory) and VIRGO (Virgo interferometer) detector networks with planned galaxy surveys should detect weak gravitational lensing of gravitational waves in the low-redshift Universe (z < 0.5). With the next-generation gravitational wave experiments such as Voyager, LISA (Laser Interferometer Space Antenna), Cosmic Explorer, and the Einstein Telescope, we can extend this test of the theory of gravity to larger redshifts by exploiting the synergies between electromagnetic wave and gravitational wave probes.
Where Are the Disease-Associated eQTLs? Umans, Benjamin D.; Battle, Alexis; Gilad, Yoav
Trends in genetics,
02/2021, Letnik:
37, Številka:
2
Journal Article
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Most disease-associated variants, although located in putatively regulatory regions, do not have detectable effects on gene expression. One explanation could be that we have not examined gene ...expression in the cell types or conditions that are most relevant for disease. Even large-scale efforts to study gene expression across tissues are limited to human samples obtained opportunistically or postmortem, mostly from adults. In this review we evaluate recent findings and suggest an alternative strategy, drawing on the dynamic and highly context-specific nature of gene regulation. We discuss new technologies that can extend the standard regulatory mapping framework to more diverse, disease-relevant cell types and states.
Mapping of regulatory quantitative trait loci (QTLs) has emerged as a powerful tool to functionally annotate noncoding DNA variants that are associated with disease risk.Large surveys of gene expression variation in healthy, adult, steady-state tissues have discovered at least one cis expression QTL (eQTL) for nearly every human gene.The properties of standard eQTLs may be inconsistent with mutations that are associated with a fitness cost, in contrast to what might be expected for mutations associated with disease.Regulatory QTL mapping during dynamic cellular processes such as differentiation and perturbation response can reveal otherwise hidden regulatory variation that may be especially relevant for disease.New platform technologies, including in vitro differentiated cell types and single-cell profiling, extend the scope of dynamic eQTL studies.
Many adverse reactions to therapeutic drugs appear to be allergic in nature, and are thought to be triggered by patient-specific Immunoglobulin E (IgE) antibodies that recognize the drug molecules ...and form complexes with them that activate mast cells. However, in recent years another mechanism has been proposed, in which some drugs closely associated with allergic-type events can bypass the antibody-mediated pathway and trigger mast cell degranulation directly by activating a mast cell-specific receptor called Mas-related G protein-coupled receptor X2 (MRGPRX2). This would result in symptoms similar to IgE-mediated events, but would not require immune priming. This review will cover the frequency, severity, and dose-responsiveness of allergic-type events for several drugs shown to have MRGPRX2 agonist activity. Surprisingly, the analysis shows that mild-to-moderate events are far more common than currently appreciated. A comparison with plasma drug levels suggests that MRGPRX2 mediates many of these mild-to-moderate events. For some of these drugs, then, MRGPRX2 activation may be considered a regular and predictable feature after administration of high doses.
Stellar Population Inference with Prospector Johnson, Benjamin D.; Leja, Joel; Conroy, Charlie ...
The Astrophysical journal. Supplement series,
06/2021, Letnik:
254, Številka:
2
Journal Article
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Abstract
Inference of the physical properties of stellar populations from observed photometry and spectroscopy is a key goal in the study of galaxy evolution. In recent years, the quality and ...quantity of the available data have increased, and there have been corresponding efforts to increase the realism of the stellar population models used to interpret these observations. Describing the observed galaxy spectral energy distributions in detail now requires physical models with a large number of highly correlated parameters. These models do not fit easily on grids and necessitate a full exploration of the available parameter space. We present
Prospector
, a flexible code for inferring stellar population parameters from photometry and spectroscopy spanning UV through IR wavelengths. This code is based on forward modeling the data and Monte Carlo sampling the posterior parameter distribution, enabling complex models and exploration of moderate dimensional parameter spaces. We describe the key ingredients of the code and discuss the general philosophy driving the design of these ingredients. We demonstrate some capabilities of the code on several data sets, including mock and real data.
A challenge for single-cell genomic studies in kidney and other solid tissues is generating a high-quality single-cell suspension that contains rare or difficult-to-dissociate cell types and is free ...of both RNA degradation and artifactual transcriptional stress responses.
We compared single-cell RNA sequencing (scRNA-seq) using the DropSeq platform with single-nucleus RNA sequencing (snRNA-seq) using sNuc-DropSeq, DroNc-seq, and 10X Chromium platforms on adult mouse kidney. We validated snRNA-seq on fibrotic kidney from mice 14 days after unilateral ureteral obstruction (UUO) surgery.
A total of 11,391 transcriptomes were generated in the comparison phase. We identified ten clusters in the scRNA-seq dataset, but glomerular cell types were absent, and one cluster consisted primarily of artifactual dissociation
induced stress response genes. By contrast, snRNA-seq from all three platforms captured a diversity of kidney cell types that were not represented in the scRNA-seq dataset, including glomerular podocytes, mesangial cells, and endothelial cells. No stress response genes were detected. Our snRNA-seq protocol yielded 20-fold more podocytes compared with published scRNA-seq datasets (2.4% versus 0.12%, respectively). Unexpectedly, single-cell and single-nucleus platforms had equivalent gene detection sensitivity. For validation, analysis of frozen day 14 UUO kidney revealed rare juxtaglomerular cells, novel activated proximal tubule and fibroblast cell states, and previously unidentified tubulointerstitial signaling pathways.
snRNA-seq achieves comparable gene detection to scRNA-seq in adult kidney, and it also has substantial advantages, including reduced dissociation bias, compatibility with frozen samples, elimination of dissociation-induced transcriptional stress responses, and successful performance on inflamed fibrotic kidney.
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