The sources of evidence contributing to metacognitive assessments of confidence in decision-making remain unclear. Previous research has shown that pupil dilation is related to the signaling of uncertainty in a variety of decision tasks. Here we ask whether pupil dilation is also related to metacognitive estimates of confidence. Specifically, we measure the relationship between pupil dilation and confidence during an auditory decision task using a general linear model approach to take into account delays in the pupillary response. We found that pupil dilation responses track the inverse of confidence before but not after a decision is made, even when controlling for stimulus difficulty. In support of an additional post-decisional contribution to the accuracy of confidence judgments, we found that participants with better metacognitive ability – that is, more accurate appraisal of their own decisions – showed a tighter relationship between post-decisional pupil dilation and confidence. Together our findings show that a physiological index of uncertainty, pupil dilation, predicts both confidence and metacognitive accuracy for auditory decisions.
Eltrombopag (ELT) is a thrombopoietin receptor agonist reported to decrease labile iron in leukemia cells. Here we examine the previously undescribed iron(III)-coordinating and cellular iron-mobilizing properties of ELT. We find a high binding constant for iron(III) (log β=35). Clinically achievable concentrations (1 µM) progressively mobilized cellular iron from hepatocyte, cardiomyocyte, and pancreatic cell lines, rapidly decreasing intracellular reactive oxygen species (ROS) and also restoring insulin secretion in pancreatic cells. Decrements in cellular ferritin paralleled total cellular iron removal, particularly in hepatocytes. Iron mobilization from cardiomyocytes exceeded that obtained with deferiprone, desferrioxamine, or deferasirox at similar iron-binding equivalents. When combined with these chelators, ELT enhanced cellular iron mobilization more than additive (synergistic) with deferasirox. Iron-binding speciation plots are consistent with ELT donating iron to deferasirox at clinically relevant concentrations. ELT scavenges iron citrate species faster than deferasirox, but rapidly donates the chelated iron to deferasirox, consistent with a shuttling mechanism. Shuttling is also suggested by enhanced cellular iron mobilization by ELT when combined with the otherwise ineffective extracellular hydroxypyridinone chelator, CP40. We conclude that ELT is a powerful iron chelator that decreases cellular iron and further enhances iron mobilization when combined with clinically available chelators.
Hydroxypyridinones (HOPOs) form outstanding building blocks for the development of a variety of agents in the field of metal chelation. The pyridinone ring is easily synthesized and readily converted into tetradentate, hexadentate, and octadentate chelators. There is considerable potential for the control of the stereochemistry of the resulting metal complex and hence the properties of these multidentate molecules. Their ability to rapidly bind hard metals in aqueous media has facilitated the development of efficient applications in both biological and medical contexts. In this Review, an in-depth analysis of the synthetic methodologies for HOPO-based ligands is presented, as well as the many aspects to achieve optimal biological activity. Recent advances and current challenges for the future application of HOPO structures are outlined. The present flourishing development of drug candidates and diagnostic agents based on this chemical scaffold opens access to many new applications in analytical, environmental, and clinical science.
Oral squamous cell carcinoma (OSCC) LN1‐1 cells previously showed greater capacities for lymphangiogenesis and lymph node metastasis compared to their parental OEC‐M1 cells, in addition to an ability to enhance the migration and tube formation of lymphatic endothelial cells (LECs). Purified by a series of differential centrifugations and characterized using electron microscopy, dynamic light scattering and western blot, LN1‐1 cell‐derived extracellular vesicles (LN1‐1 EVs) were shown to promote LEC migration, tube formation and uptake by LECs more effectively than did OEC‐M1 cell‐derived EVs (OEC‐M1 EVs). Using stable isotope labeling with amino acids in cell culture/liquid chromatography–tandem mass spectrometry‐based proteomic platform, the laminin‐332 proteins, including laminin α3, β3 and γ2, were validated as highly expressed proteins in LN1‐1 EVs. Clinically, a higher level of laminin‐332 was detected in plasma EVs from OSCC patients with lymph node metastasis than in both healthy controls and OSCC patients without lymphatic metastasis, suggesting EV‐borne laminin‐332 as a novel and noninvasive biomarker for the detection of lymph node metastasis in OSCC. The knockdown of laminin γ2 and inhibition by anti‐laminin‐332 neutralizing antibodies impaired LN1‐1 EV‐mediated LEC migration, tube formation and uptake by LECs. Importantly, laminin γ2‐deficient EVs showed a reduced ability to drain into lymph nodes in comparison with the control EVs. In addition, the laminin 332/γ2‐mediated EV uptake was dependent on integrin α3 but not β1, β4 or α6. Collectively, the uptake of laminin γ2‐enriched EVs by LECs enhanced in vitro lymphangiogenesis and EV‐borne laminin‐332 is thus a viable biomarker for OSCC.
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