Extracellular protein disulfide isomerase (PDI) is a
promising
target for thrombotic-related diseases. Four potent PDI inhibitors
with unprecedented chemical architectures, piericones A–D (1–4), were isolated from Pieris japonica. Their structures were elucidated by spectroscopic data analysis,
chemical methods, quantum 13C nuclear magnetic resonance
DP4+ and electronic circular dichroism calculations, and single-crystal
X-ray diffraction analysis. Piericones A (1) and B (2) were nanomolar noncompetitive PDI inhibitors possessing
an unprecedented 3,6,10,15-tetraoxatetracyclo[7.6.0.04,9.01,12]pentadecane motif with nine contiguous stereogenic
centers. Their biosynthetic pathways were proposed to include a key
intermolecular aldol reaction and an intramolecular 1,2-migration
reaction. Piericone A (1) significantly inhibited in
vitro platelet aggregation and fibrin formation and in vivo thrombus
formation via the inhibition of extracellular PDI without increasing
the bleeding risk. The molecular docking and dynamics simulation of 1 and 2 provided a novel structure basis to develop
PDI inhibitors as potent antithrombotics.
Pragmatic information, such as inferences regarding upcoming coreference, has been shown to influence phonetic perception (Rohde & Ettlinger, 2012). Pragmatic information, however, comes in many forms. Using a Visual World Paradigm, tracking listeners' categorical responses and the time-course of information integration via eye movements, we investigated whether and how a different kind of pragmatic information, the contrastive function of prenominal adjectives (Sedivy, Tanenhaus, Chambers, & Carlson, 1999), can affect listeners' perception of voicing in initial plosives. Our results suggest that the pragmatic contrast inference did not affect the behavioral judgments on phonetic categorization, but it did have an (albeit limited) influence during the online processing of voice onset time (VOT). Our findings suggest that different kinds of higher-level pragmatic inferences are not uniform in how (successfully) they are integrated with low-level phonetic properties in real-time comprehension.
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