Understanding kidney disease relies upon defining the complexity of cell types and states, their associated molecular profiles, and interactions within tissue neighborhoods. We have applied multiple single-cell or -nucleus assays (>400,000 nuclei/cells) and spatial imaging technologies to a broad spectrum of healthy reference (n = 42) and disease (n = 42) kidneys. This has provided a high resolution cellular atlas of 100 cell types that include rare and novel cell populations. The multi-omic approach provides detailed transcriptomic profiles, epigenomic regulatory factors, and spatial localizations for major cell types spanning the entire kidney. We further identify and define cellular states altered in kidney injury, encompassing cycling, adaptive or maladaptive repair, transitioning and degenerative states affecting several segments. Molecular signatures of these states permitted their localization within injury neighborhoods using spatial transcriptomics, and large-scale 3D imaging analysis of ~1.2 million neighborhoods provided linkages to active immune responses. These analyses further defined biological pathways relevant to injury niches, including signatures underlying the transition from reference to predicted maladaptive states that were associated with a decline in kidney function during chronic kidney disease. This human kidney cell atlas, including injury cell states and neighborhoods, will be a valuable resource for future studies.
A novel use of the electron backscattered diffraction (EBSD) characterization technique for study of fracture has been demonstrated. This new approach has been employed for characterization and analysis that contribute to the understanding of crack initiation in Ti-6242 under dwell-fatigue loading conditions. A faceted crack initiation site is typically observed on the dwell-fatigue fracture surface of Ti-6242. The level of microtexture has a major influence on the dwell-fatigue failures in near-␣ titanium alloys, such as Ti-6242. In this study, serial sectioning and EBSD techniques were used to obtain the orientation images of almost the entire specimen cross section at different depths below the fracture surface. The orientation images are color coded on three different bases: the angle between the loading axis and basal plane normal, the Schmid factor for prism slip, and the Schmid factor for basal slip. The aim was to determine the important aspects of the crystallographic orientation and the size of the microtextured region that is associated with the faceted initiation site. The results of this study are used to explain the possible locations of crack initiation in a test specimen under dwell-fatigue loading condition. These results are also used to better understand the role of size of microtextured regions in determining which crack will outgrow the other cracks (for the case of multiple cracking typically observed in the alloy of current study under the dwell-fatigue loading conditions) to become the dominant crack that leads to eventual specimen failure. This understanding has important practical implications because the dominant crack effectively determines the specimen life.
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