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Background: Oral ingestion, inhalation, and skin contact are important exposure routes for humans to uptake per- and polyfluoroalkyl substances (PFAS). However, nasal and dermal exposure to PFAS remains unclear, and accurately predicting internal body burden of PFAS in humans via multiple exposure pathways is urgently required. Objectives: We aimed to develop multiple physiologically based toxicokinetic (PBTK) models to unveil the route- specific pharmacokinetics and bioavailability of PFAS via respective oral, nasal, and dermal exposure pathways using a mouse model and sought to predict the internal concentrations in various tissues through multiple exposure routes and extrapolate it to humans. Methods: Mice were administered the mixed solution of perfluorohexane sulfonate, perfluorooctane sulfonate, and perfluorooctanoic acid through oral, nasal, and dermal exposure separately or jointly. The time-dependent concentrations of PFAS in plasma and tissues were determined to calibrate and validate the individual and combined PBTK models, which were applied in single- and repeated-dose scenarios. Results: The developed route-specific PBTK models successfully simulated the tissue concentrations of PFAS in mice following single or joint exposure routes as well as long-term repeated dose scenarios. The time to peak concentration of PFAS in plasma via dermal exposure was much longer (34.1-83.0 h) than that via nasal exposure (0.960 h). The bioavailability of PFAS via oral exposure was the highest (73.2%-98.0%), followed by nasal (33.9%-66.8%) and dermal exposure (4.59%-7.80%). This model was extrapolated to predict internal levels in human under real environment. Discussion: Based on these data, we predict the following: PFAS were absorbed quickly via nasal exposure, whereas a distinct hysteresis effect was observed for dermal exposure. Almost all the PFAS to which mice were exposed via gastrointestinal route were absorbed into plasma, which exhibited the highest bioavailability. Exhalation clearance greatly depressed the bioavailability of PFAS via nasal exposure, whereas the lowest bioavailability in dermal exposure was because of the interception of PFAS within the skin layers. https://doi.org/10.1289/EHP11969, Introduction Since the 1950s, per- and polyfluoroalkyl substances (PFAS) have been widely used in a variety of industrial and household fields owing to their excellent surface activity, thermal and chemical [...]

Intervertebral disc degeneration (IVDD) is a general disorder that results in low back pain and disability among many affected individuals. However, the current treatments for IVDD are limited to relieving the symptoms but do not solve the fundamental issue. In this study, the role of USP14 in mediating the activation of the NLRP3 inflammasome and the pyroptosis of AF cells from IVDD patients is determined in vitro, and gain- and loss-of-function assays of USP14 and the NLRP3 inflammasome are conducted. Pyroptosis of AF cells is detected by flow cytometry. The inflammatory cytokines (IL-1β and IL-18) and protein levels of NLRP3, active Caspase-1, Aggrecan, MMP3 and ADAMTS-5 are determined by ELISA and western blot analysis, respectively. The correlation between USP14 and NLRP3 is measured by coimmunoprecipitation and ubiquitination analysis. Upregulation of USP14 is accompanied by increased level of the NLRP3 inflammasome in AF cells from IVDD patients; furthermore, a positive correlation between them is observed. USP14 knockdown inhibits pyroptosis in AF cells by inducing ubiquitination of NLRP3, while overexpression of USP14 has the opposite effect, which is inhibited by the NLRP3 inflammasome inhibitor INF39. USP14 exerts its positive regulatory effect on AF cell pyroptosis by modulating the NLRP3/Caspase-1/IL-1β and IL-18 signaling axes.

A series of (Ba0.2Sr0.2Na0.2Ca0.2La0.2)(ZrxTi1‐x)O3 (BSNCLZxT1‐x) (x = 0, 0.05, 0.1, 0.15, and 0.2) high‐entropy ceramics were prepared in forms of bulks and thin films by conventional sintering and spin‐coating, respectively. All ceramic bulks and thin films are composed of a single perovskite‐structured solid solution. The introduction of the Zr element reduces the dielectric loss of bulks and thin films and improves the frequency stability of the dielectric constant. The ceramic bulks have a higher dielectric constant and lower loss than their corresponding thin films. As x rises from 0 to 0.2, the breakdown strength Eb of the ceramic bulks increases from 209 to 327 kV/cm, and that of thin films enhances from 890 to 1770 kV/cm. The bulks and thin films of BSNCLZ0.1T0.9 possess the maximum recoverable energy density Wrec (0.82 and 3.48 J/cm3) and energy storage efficiency η (95.8% and 86.8%). [ABSTRACT FROM AUTHOR]

Machine vision is a desirable non-contact measurement method for hot forgings, as image segmentation has been a challenging issue in performance and robustness resulting from the diversity of working conditions for hot forgings. Thus, this paper proposes an efficient and robust active contour model and corresponding image segmentation approach for forging images, by which verification experiments are conducted to prove the performance of the segmentation method by measuring geometric parameters for forging parts. Specifically, three types of continuity parameters are defined based on the geometric continuity of equivalent grayscale surfaces for forging images; hence, a new image force and external energy functional are proposed to form a new active contour model, Geometric Continuity Snakes (GC Snakes), which is more percipient to the grayscale distribution characteristics of forging images to improve the convergence for active contour robustly; additionally, a generating strategy for initial control points for GC Snakes is proposed to compose an efficient and robust image segmentation approach. The experimental results show that the proposed GC Snakes has better segmentation performance compared with existing active contour models for forging images of different temperatures and sizes, which provides better performance and efficiency in geometric parameter measurement for hot forgings. The maximum positioning and dimension errors by GC Snakes are 0.5525 mm and 0.3868 mm, respectively, compared with errors of 0.7873 mm and 0.6868 mm by the Snakes model. [ABSTRACT FROM AUTHOR]

Early after entry into monocytes, macrophages, dendritic cells, and resting CD4 T cells, HIV encounters a block, limiting reverse transcription (RT) of the incoming viral RNA genome. In this context, dNTP triphosphohydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) has been identified as a restriction factor, lowering the concentration of dNTP substrates to limit RT. The accessory lentiviral protein X (Vpx) proteins from the major simian immunodeficiency virus of rhesus macaque, sooty mangabey, and HIV-2 (SIVsmm/SIVmac/HIV-2) lineage packaged into virions target SAMHD1 for proteasomal degradation, increase intracellular dNTP pools, and facilitate HIV cDNA synthesis. We find that virion-packaged Vpx proteins from a second SIV lineage, SIV of red-capped mangabeys or mandrills (SIVrcm/mnd-2), increased HIV infection in resting CD4 T cells, but not in macrophages, and, unexpectedly, acted in the absence of SAMHD1 degradation, dNTP pool elevation, or changes in SAMHD1 phosphorylation. Vpx rcm/mnd-2 virion incorporation resulted in a dramatic increase of HIV-1 RT intermediates and viral cDNA in infected resting CD4 T cells. These analyses also revealed a barrier limiting HIV-1 infection of resting CD4 T cells at the level of nuclear import. Single amino acid changes in the SAMHD1-degrading Vpx mac239 allowed it to enhance early postentry steps in a Vpx rcm/mnd-2-like fashion. Moreover, Vpx enhanced HIV-1 infection of SAMHD1-deficient resting CD4 T cells of a patient with Aicardi-Goutières syndrome. These results indicate that Vpx, in addition to SAMHD1, overcomes a previously unappreciated restriction for lentiviruses at the level of RT that acts independently of dNTP concentrations and is specific to resting CD4 T cells.