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Rationale: Pyroptosis is a morphologically and mechanistically distinct form of cell death and is characterized by gasdermin D (GSDMD) or gasdermin E (GSDME)-mediated necrosis with excessive inflammatory factor release. Cardiomyocyte necrosis and inflammation play key roles in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury. However, whether cardiomyocytes undergo pyroptosis and the underlying mechanism in myocardial I/R injury remain unclear. Objective: We aimed to investigate the role of pyroptosis in myocardial I/R injury. Methods and Results: In vivo and in vitro experiments were used to investigate pyroptosis of cardiomyocyte and the associated mechanisms during I/R injury. Wild-type (WT), Myh6-Cre and cardiomyocyte-specific GSDMD-deficient (GSDMD-CKO) male mice were subjected to I/R. Human peripheral blood samples were collected from STEMI (acute ST-segment-elevation myocardial infarction) patients or control patients at 0, 1 and 24 h after PCI (percutaneous coronary intervention) in our department. The serum levels of GSDMD were measured by ELISA. H/R (hypoxia/reoxygenation) induced cardiomyocyte pyroptosis and the release of mature IL-18 but not IL-1β, which mechanistically resulted from GSDMD cleavage by caspase-11 in cardiomyocytes. Furthermore, GSDMD gene deletion blocked H/R-induced cardiomyocyte pyroptosis and IL-18 release. GSDMD and its pyroptosis-inducing N-terminal fragment (GSDMD-N) were upregulated in myocardial tissues after I/R injury. Immunofluorescence analysis showed that GSDMD was mainly localized in cardiomyocytes. GSDMD deficiency in cardiomyocytes significantly reduced the I/R-induced myocardial infarct size. Moreover, increased GSDMD serum levels were detected in patients exhibiting I/R injury 1 h after PCI for STEMI. Conclusions: Our results show that GSDMD-mediated cardiomyocyte pyroptosis is a key event during myocardial I/R injury and that the caspase-11/GSDMD pathway may be essential to this process. Additionally, GSDMD inhibition significantly reduces cardiomyocyte pyroptosis and I/R-induced myocardial injury.

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Background and objectivesInvoluntary autobiographical memories that spring unbidden into conscious awareness form part of everyday experience. In psychopathology, involuntary memories can be associated with significant distress. However, the cognitive mechanisms associated with the development of involuntary memories require further investigation and understanding. Since involuntary autobiographical memories are image-based, we tested predictions that visuospatial (but not other) established cognitive tasks could disrupt their consolidation when completed post-encoding.MethodsIn Experiment 1, participants watched a stressful film then immediately completed a visuospatial task (complex pattern tapping), a control-task (verbal task) or no-task. Involuntary memories of the film were recorded for 1-week. In Experiment 2, the cognitive tasks were administered 30-min post-film.ResultsCompared to both control and no-task conditions, completing a visuospatial task post-film reduced the frequency of later involuntary memories (Expts 1 and 2) but did not affect voluntary memory performance on a recognition task (Expt 2).LimitationsVoluntary memory was assessed using a verbal recognition task and a broader range of memory tasks could be used. The relative difficulty of the cognitive tasks used was not directly established.ConclusionsAn established visuospatial task after encoding of a stressful experience selectively interferes with sensory-perceptual information processing and may therefore prevent the development of involuntary autobiographical memories.

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Amyloids are insoluble, fibrous proteins formed through the aggregation of misfolded proteins. They accumulate in the tissue of individuals with degenerative diseases, such as Parkinson's and Alzheimer's. The purpose of this study was to determine whether fibril growth from an initial model fibril seed is unidirectional or bidirectional. The prevailing theory on amyloid formation is that a symmetric fibril elongates equally from both ends. This study provides evidence to the contrary; the process occurs predominately unidirectionally, demonstrating that amyloid fibrils may be asymmetric and propagate mostly in one direction. Alexa Fluor 568 labeled insulin fibrils were seeded into a native insulin solution and allowed to elongate at 65°C while the kinetics of fibril growth was monitored. The resulting elongated fibrils were labeled with thioflavin-T, and the fluorescent images of the fibrils show that a majority of the elongated fibrils propagated along only one end of the seed, with the remaining labeled fibrils having bidirectional elongation or no elongation. Using a crystallographic model, we offer a structural explanation for asymmetric growth of the insulin fibrils. Thus, instead of the current view that fibrils grow symmetrically from both ends of the fibril, this is the first evidence that insulin amyloid fibrils formed in solution are asymmetric and appear to grow from only one end.