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SUMMARY Cerebral cavernous malformations (CCMs) are a cause of stroke and seizure for which no medical therapies exist. CCMs arise from loss of an adaptor complex that negatively regulates MEKK3-KLF2/4 signaling in brain endothelial cells, but upstream activators of this disease pathway remain unknown. Here, we identify endothelial TLR4 and the gut microbiome as critical stimulants of CCM formation. Activation of TLR4 by gram negative bacteria or lipopolysaccharide accelerates CCM formation, while genetic or pharmacologic blockade of TLR4 signaling prevents CCM formation in mice. Polymorphisms that increase expression of TLR4 or its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signaling in the pathogenesis of a cerebrovascular disease, as well as novel strategies for its treatment.

Traditionally, ritual has been studied from broad sociocultural perspectives, with little consideration of the psychological processes at play. Recently, however, psychologists have begun turning their attention to the study of ritual, uncovering the causal mechanisms driving this universal aspect of human behavior. With growing interest in the psychology of ritual, this article provides an organizing framework to understand recent empirical work from social psychology, cognitive science, anthropology, behavioral economics, and neuroscience. Our framework focuses on three primary regulatory functions of rituals: regulation of (a) emotions, (b) performance goal states, and (c) social connection. We examine the possible mechanisms underlying each function by considering the bottom-up processes that emerge from the physical features of rituals and top-down processes that emerge from the psychological meaning of rituals. Our framework, by appreciating the value of psychological theory, generates novel predictions and enriches our understanding of ritual and human behavior more broadly.

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