Whole-genome sequencing (WGS) of human tumors and normal cells exposed to various carcinogens has revealed distinct mutational patterns that provide deep insights into the DNA damage and repair processes. Although ionizing radiation (IR) is conventionally known as a strong carcinogen, its genome-wide mutational impacts have not been comprehensively investigated at the single-nucleotide level. Here, we explored the mutational landscape of normal single-cells after exposure to the various levels of IR. On average, 1 Gy of IR exposure generated ∼16 mutational events with a spectrum consisting of predominantly small nucleotide deletions and a few characteristic structural variations. In ∼30% of the post-irradiated cells, complex genomic rearrangements, such as chromoplexy, chromothripsis, and breakage-fusion-bridge cycles, were resulted, indicating the stochastic and chaotic nature of DNA repair in the presence of the massive number of concurrent DNA double-strand breaks. These mutational signatures were confirmed in the genomes of 22 IR-induced secondary malignancies. With high-resolution genomic snapshots of irradiated cells, our findings provide deep insights into how IR-induced DNA damage and subsequent repair processes operate in mammalian cells.
Cerebral microinfarct increases the risk of dementia. But how microscopic cerebrovascular disruption affects the brain tissue in cellular-level are mostly unknown.Herein, with a longitudinal intravital imaging, we serially visualized in vivo dynamic cellular-level changes in astrocyte, pericyte and neuron as well as microvascular integrity after the induction of cerebral microinfarction for 1 month in mice. At day 2-3, it revealed a localized edema with acute astrocyte loss, neuronal death, impaired pericyte-vessel coverage and extravascular leakage of 3 kDa dextran (but not 2 MDa dextran) indicating microinfarction-related blood-brain barrier (BBB) dysfunction for small molecules. At day 5, the local edema disappeared with the partial restoration of microcirculation and recovery of pericyte-vessel coverage and BBB integrity. But brain tissue continued to shrink with persisted loss of astrocyte and neuron in microinfarct until 30 days, resulting in a collagen-rich fibrous scar surrounding the microinfarct. Notably, reactive astrocytes expressing glial fibrillary acidic protein (GFAP) appeared at the peri-infarct area early at day 2 and thereafter accumulated in the peri-infarct until 30 days, inducing glial scar formation in cerebral cortex. Our longitudinal intravital imaging of serial microscopic neurovascular pathophysiology in cerebral microinfarction newly revealed that astrocytes are critically susceptible to the acute microinfarction and their reactive response leads to the fibrous glial scar formation.
High‐resolution structural imaging of brain tissue is important for neuroscience research. However, conventional approaches have several limitations, such as the need for exogenous staining, limited accessibility to volumetric information, and qualitative analysis. Herein, high‐resolution label‐free volumetric imaging and analysis of mouse brain tissue are presented using 3D quantitative phase imaging. Measurement of the refractive index distribution of tissue enables direct imaging of the cellular and subcellular structures. Quantification of subcellular organelles is performed in the anatomical regions of the somatosensory cortex, corpus callosum, caudoputamen, and thalamus regions.
High-resolution structural imaging of brain tissue is important for neuroscience research. However, conventional approaches have several limitations, such as the need for exogenous staining, limited accessibility to volumetric information, and qualitative analysis. Herein, we present high-resolution label-free volumetric imaging and analysis of mouse brain tissue using three-dimensional quantitative phase imaging. Measurement of the refractive index distribution of tissue enables direct imaging of the cellular and subcellular structures. Quantification of subcellular organelles is performed in the anatomical regions of the somatosensory cortex, corpus callosum, caudoputamen, and thalamus regions.
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