英語関係代名詞whichの機能と習得 : コーパスに基づく記述的研究

<div><p></p><p>An estimated 1% or less of nanoparticles (NPs) deposited in the lungs translocate to systemic circulation and enter other organs; however, this estimation may not be accurate given the low sensitivity of existing <i>in vivo</i> NP detection methods. Moreover, the biological effects of such low levels of translocation are unclear. We employed a nano-scale hyperspectral microscope to spatially observe and spectrally profile NPs in tissues and blood following pulmonary deposition in mice. In addition, we characterized effects occurring in blood, liver and heart at the mRNA and protein level following translocation from the lungs. Adult female C57BL/6 mice were exposed via intratracheal instillation to 18 or 162 µg of industrially relevant titanium dioxide nanoparticles (nano-TiO₂) alongside vehicle controls. Using the nano-scale hyperspectral microscope, translocation to heart and liver was confirmed at both doses, and to blood at the highest dose, in mice analyzed 24 h post-exposure. Global gene expression profiling and ELISA analysis revealed activation of complement cascade and inflammatory processes in heart and specific activation of complement factor 3 in blood, suggesting activation of an early innate immune response essential for particle opsonisation and clearance. The liver showed a subtle response with changes in the expression of genes associated with acute phase response. This study characterizes the subtle systemic effects that occur in liver and heart tissues following pulmonary exposure and low levels of translocation of nano-TiO₂ from lungs.</p></div

Gene network.

<p>Combined analysis of all significantly differentially expressed genes associated with angiogenesis, lipid metabolism, and cellular proliferation pathways in lungs in the high dose group. Analysis was conducted and the network was built using GeneGo Metacore map creator. The figure shows that the majority of the genes are commonly regulated by <i>E2f1</i>, <i>Il6</i> and <i>C-myc</i>. Hexagons represent physical and functional interactions: TR – transcription regulation, IE - influence on expression, B – binding, and GR – group. The green arrows represent positive regulation/activation, the brown arrows represent negative regulation/inhibition and the grey arrows represent unspecified regulation.</p

The total number of genes perturbed in the categories of gene expression and cellular signalling functions.

<p>Green: low dose (12.5 µg <i>in </i><i>vitro</i>, 18 µg <i>in </i><i>vivo</i>), blue: medium dose (25 µg <i>in </i><i>vitro</i>, 54 µg <i>in </i><i>vivo</i>), and red: high dose (100 µg <i>in </i><i>vitro</i>, 162 µg <i>in </i><i>vivo</i>). </p

Light microscopy images of Mitsui7 dispersed in the <i>in</i><i>vitro</i> exposure medium after sonication.

<p>(A) 100 μg/milliliter (31.19 µg/cm²) concentration (B) 12.5 μg/ml concentration (3.9 µg/cm²). Bars represent 50μm.</p

SEM images of dry, pristine Mitsui7.

<p>(A) Mitsui7 at high density. (B) A close-up of MWCNT at high density. (C) Mitsui7 behavior at low density.</p

Gene heatmap comparing differentially expressed genes in the categories of fibrosis, inflammation and oxidative stress.

<p>Red represents up-regulation, green represents down-regulation and grey represents no change in the expression. </p

Top three biological networks <i>in</i><i>vitro</i>.

<p>The networks were generated by merging the top three networks in each of the dose and were based on the connectivity between each gene and the molecular interaction knowledge base in IPA. Nodes are highlighted in large bold font. Green indicates down-regulation and red indicates up-regulation.</p

Overview of response in FE1 cells.

<p>(A) Venn diagram showing the overlapping differentially expressed genes (FDR P ≤ 0.05 and fold change ≥ 1.5) in response to low (12.5 µg, green), medium (25 µg, blue), and high (100 µg, red) doses of Mitsui7 <i>in </i><i>vitro</i>. (B-C) Gene ontology (GO) analysis of differentially expressed genes. (B) Commonly regulated GO biological processes (C) GO biological processes unique to the high dose group. Numbers in parentheses represent number of genes altered in that process.</p

Differentially expressed genes associated with five top canonical pathways derived from IPA analysis.

<p><b>Genes </b><b>are </b><b>categorized </b><b>into </b><b>four </b><b>major </b><b>functions</b> (cell cycle regulation-orange, xenobiotic metabolism-green, inflammation-violet, and tissue fibrosis-blue). All genes in both models are regulated by a common transcription factor, AHR. Genes highlighted with green indicate down-regulation and genes highlighted with red indicate up-regulation. The transcription factor AHR is down-regulated in cells, suggesting negative regulation of the downstream functions in cells. </p

Comparison of biological functions and networks altered <i>in</i><i>vitro</i> and <i>in</i><i>vivo</i>.

<p>Top 10 biological functions altered in lung epithelial cells (A, C, E) and in the lung tissue (B, D, F). The spatial visualization of gene network associated with the biological functions cellular growth and proliferation (C-D) and cancer (E-F). Grey lines connect the significantly differentially expressed genes to the annotation terms associated with each biological function. </p