Hepatocytes and the art of killing Plasmodium softly.

The Plasmodium parasites that cause malaria undergo asymptomatic development in the parenchymal cells of the liver, the hepatocytes, prior to infecting erythrocytes and causing clinical disease. Traditionally, hepatocytes have been perceived as passive bystanders that allow hepatotropic pathogens such as Plasmodium to develop relatively unchallenged. However, now there is emerging evidence suggesting that hepatocytes can mount robust cell-autonomous immune responses that target Plasmodium, limiting its progression to the blood and reducing the incidence and severity of clinical malaria. Here we discuss our current understanding of hepatocyte cell-intrinsic immune responses that target Plasmodium and how these pathways impact malaria.

Inherently Reduced Expression of ASC Restricts Caspase-1 Processing in Hepatocytes and Promotes Plasmodium Infection.

Inflammasome-mediated caspase-1 activation facilitates innate immune control of Plasmodium in the liver, thereby limiting the incidence and severity of clinical malaria. However, caspase-1 processing occurs incompletely in both mouse and human hepatocytes and precludes the generation of mature IL-1ß or IL-18, unlike in other cells. Why this is so or how it impacts Plasmodium control in the liver has remained unknown. We show that an inherently reduced expression of the inflammasome adaptor molecule apoptosis-associated specklike protein containing CARD (ASC) is responsible for the incomplete proteolytic processing of caspase-1 in murine hepatocytes. Transgenically enhancing ASC expression in hepatocytes enabled complete caspase-1 processing, enhanced pyroptotic cell death, maturation of the proinflammatory cytokines IL-1ß and IL-18 that was otherwise absent, and better overall control of Plasmodium infection in the liver of mice. This, however, impeded the protection offered by live attenuated antimalarial vaccination. Tempering ASC expression in mouse macrophages, on the other hand, resulted in incomplete processing of caspase-1. Our work shows how caspase-1 activation and function in host cells are fundamentally defined by ASC expression and offers a potential new pathway to create better disease and vaccination outcomes by modifying the latter.

Force decay of polyethylene terephthalate glycol aligner materials during simulation of typical clinical loading/unloading scenarios.

BACKGROUND: This in vitro study investigated the effect of three distinct daily loading/unloading cycles on force delivery during orthodontic aligner therapy. The cycles were applied for 7 days and were designed to reflect typical clinical aligner application scenarios. MATERIALS AND METHODS: Flat polyethylene terephthalate glycol (PET-G) specimens (Duran®, Scheu Dental, Iserlohn, Germany) with thicknesses ranging between 0.4 and 0.75 mm were tested in a three-point-bending testing machine. Measurements comprised loading/unloading intervals of 12 h/12 h, 18 h/6 h, and 23 h/1 h, and specimens were exposed to bidistilled water during loading to simulate intraoral conditions. RESULTS: A very large decay in force for the PET­G specimens could already be observed after the first loading period, with significantly different residual force values of 24, 20, and 21% recorded for the 12 h/12 h, 18 h/6 h, and 23 h/1 h loading/unloading modes, respectively (Mann-Whitney U test, p < 0.01). In addition, further decays in force from the first to the last loading period at day 7 of 13.5% (12 h/12 h), 9.7% (18 h/6 h), and 8.4% (23 h/1 h) differed significantly among the three distinct loading modes (Mann-Whitney U test, p < 0.01). CONCLUSION: Although the initial material stiffness of PET­G is relatively high, the transmission of excessive forces is attenuated by the high material-related force decay already within a few hours after intraoral insertion.