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Vascular malformations are thought to be monogenic disorders that result in dysregulated growth of blood vessels. In the brain, cerebral cavernous malformations (CCMs) arise owing to inactivation of the endothelial CCM protein complex, which is required to dampen the activity of the kinase MEKK3 1 – 4 . Environmental factors can explain differences in the natural history of CCMs between individuals 5 , but why single CCMs often exhibit sudden, rapid growth, culminating in strokes or seizures, is unknown. Here we show that growth of CCMs requires increased signalling through the phosphatidylinositol-3-kinase (PI3K)–mTOR pathway as well as loss of function of the CCM complex. We identify somatic gain-of-function mutations in PIK3CA and loss-of-function mutations in the CCM complex in the same cells in a majority of human CCMs. Using mouse models, we show that growth of CCMs requires both PI3K gain of function and CCM loss of function in endothelial cells, and that both CCM loss of function and increased expression of the transcription factor KLF4 (a downstream effector of MEKK3) augment mTOR signalling in endothelial cells. Consistent with these findings, the mTORC1 inhibitor rapamycin effectively blocks the formation of CCMs in mouse models. We establish a three-hit mechanism analogous to cancer, in which aggressive vascular malformations arise through the loss of vascular ‘suppressor genes’ that constrain vessel growth and gain of a vascular ‘oncogene’ that stimulates excess vessel growth. These findings suggest that aggressive CCMs could be treated using clinically approved mTORC1 inhibitors. Aggressive cerebral cavernous malformations (CCMs) are found to grow through a three-hit cancer-like mechanism, involving gain of function of a gene that promotes vascular growth, and loss of function of genes that suppress it.

Long-established rituals in preexisting cultural groups have been linked to the cultural evolution of group cooperation. We tested the prediction that novel rituals—arbitrary hand and body gestures enacted in a stereotypical and repeated fashion—can inculcate intergroup bias in newly formed groups. In four experiments, participants practiced novel rituals at home for 1 week (Experiments 1, 2, and 4) or once in the lab (Experiment 3) and were divided into minimal in-groups and out-groups. Our results offer mixed support for the hypothesis that novel rituals promote intergroup bias. Specifically, we found a modest effect for daily repeated rituals but a null effect for rituals enacted only once. These results suggest that novel rituals can inculcate bias, but only when certain features are present: Rituals must be sufficiently elaborate and repeated to lead to bias. Taken together, our results offer modest support that novel rituals can promote intergroup bias.

Cerebral cavernous malformations (CCMs) are a cause of stroke and seizure for which no effective medical therapies yet exist. CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3–KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified. Here we identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of CCM formation. Activation of TLR4 by Gram-negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding 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 signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment. Lipopolysaccharide derived from gut bacteria can accelerate the formation of cerebral cavernous malformations by activating TLR4 on endothelial cells, and polymorphisms that increase expression of the genes encoding TLR4 or its co-receptor CD14 are associated with higher CCM lesion burden in humans. Microbiome driven cerebral malformations Cerebral cavernous malformations (CCMs) are malformations of the vascular system, seen mainly in the brain where they can cause haemorrhagic stroke and seizures. CCMs arise from loss-of-function mutations in components of a complex that negatively regulates MEKK3–KLF2/4 signalling and Rho/ROCK signalling in brain endothelial cells. Mark Kahn and colleagues now identify upstream regulators that activate this pathway in brain endothelial cells. They find that lipopolysaccharide derived from gut bacteria can accelerate CCM formation by activating TLR4 on endothelial cells. The authors further show that polymorphisms in the TLR4 gene or CD14 , the gene encoding its co-receptor, are associated with higher CCM lesion burden in humans. These findings suggest that the gut microbiome and TLR4 are important drivers of CCMs and represent potential therapeutic targets.

The target article develops an account of religious prosociality that is driven by increases in self-control. We suggest this account is incomplete. Although religion might increase prosociality to the in-group, it decreases it to the much larger out-group. Rituals, for example, lead to out-group derogation. We also challenge the link between religion and improved self-control, offering evidence that religion hinders self-control.

Much of human learning happens in the social world. A person’s social identity—the groups to which they belong, the people with whom they identify—is a powerful cue that can affect our goal-directed behaviors, often implicitly. In the present experiment, we explored the underlying neural mechanisms driving these processes, testing hypotheses derived from social identity theory. In a within-subjects design, participants underwent a minimal group manipulation where they were randomly assigned to an arbitrary ingroup. In two blocks of the experiment, participants were asked to complete a task for money while being observed by an ingroup member and outgroup member separately. Results revealed that being observed by an ingroup or outgroup member led to divergent patterns of neural activity associated with feedback monitoring, namely the feedback-related negativity (FRN). Receiving feedback in the presence of an ingroup member produced a typical FRN signal, but the FRN was dampened while receiving feedback in the presence of an outgroup member. Further, this differentiated neural pattern was exaggerated in people who reported greater intergroup bias. Together, the mere presence of a person can alter how the brain adaptively monitors feedback, impairing the reinforcement learning signal when the person observing is an outgroup member.

Rituals are found in all types of performance domains, from high-stakes athletics and military to the daily morning preparations of the working family. Yet despite their ubiquity and widespread importance for humans, we know very little of ritual’s causal basis and how (if at all) they facilitate goal-directed performance. Here, in a fully pre-registered pre/post experimental design, we examine a candidate proximal mechanism, the error-related negativity (ERN), in testing the prediction that ritual modulates neural performance-monitoring. Participants completed an arbitrary ritual—novel actions repeated at home over one week—followed by an executive function task in the lab during electroencephalographic (EEG) recording. Results revealed that relative to pre rounds, participants showed a reduced ERN in the post rounds, after completing the ritual in the lab. Despite a muted ERN, there was no evidence that the reduction in neural monitoring led to performance deficit (nor a performance improvement). Generally, the findings are consistent with the longstanding view that ritual buffers against uncertainty and anxiety. Our results indicate that ritual guides goal-directed performance by regulating the brain’s response to personal failure.

Superparamagnetic iron oxide nanoparticles (SPIONs) have been used as magnetic resonance imaging (MRI) contrast agents; however, a number of T2-weighted imaging SPIONs have been withdrawn due to their poor clinical contrast performance. Our aim was to significantly improve SPION T2-weighted MRI contrast by clustering SPIONs within novel chitosan amphiphiles. Clustering SPIONs was achieved by encapsulation of hydrophobic-coated SPIONs with an amphiphilic chitosan polymer (GCPQ). Clustering increases the spin-spin ( ) to spin-lattice ( ) relaxation ratio ( ) from 3.0 to 79.1, resulting in superior contrast. Intravenously administered clustered SPIONs accumulated only in the liver and spleen; with the reduction in T2 relaxation confined, in the liver, to the extravascular space, giving clear MRI images of the liver vasculature.

Oldenburg and coworkers [2] showed that propranolol decreased lesion development and rescued barrier function in CCMs in Ccm3/(Pdcd10)iECKO model of CCM disease when given propranolol orally at 12.5 mg/kg/day (equivalent to 70 mg/day for a 70 kg human adult [3, 4]) up to age P21 via mother’s milk, and then at 100 mg/kg/day (equivalent to 560 mg/day for a 70 kg human adult [3, 4]) from ages P21 to P28. Methods to acquire and analyze data for hemodynamics (contractility and heart rate), lesion burden (percent lesion volume per mouse brain volume, primary outcome), acute and chronic hemorrhage, and attrition were described previously [5]. Propranolol treatment at 15 mg/kg/day did not affect CCM lesion burden (Fig. 1c, d), acute hemorrhage (Fig. 1e), chronic hemorrhage (scant Perls stained non-heme iron in 4 out of 29 placebo and in 2 out of 26 propranolol treated mice) nor attrition (Fig. 1f).

The Patient-Reported Outcomes, Burdens, and Experiences (PROBE) questionnaire is a tool for assessing the quality of life and disease burden in people living with hemophilia. The objectives of our study were (1) to assess the needs of relevant stakeholders involved in the use of PROBE, (2) to develop the software infrastructure needed to meet these needs, and (3) to test the usability of the final product. We conducted a series of semistructured interviews of relevant stakeholders, including PROBE investigators, people with hemophilia, and representatives of the sponsor. Based on these, we developed an online survey and a mobile app for iOS and Android. A user group evaluated the final product using the System Usability Scale (SUS) and an open feedback framework. The online survey was updated, and the myPROBE app for mobile devices and a new application programming interface were developed. The app was tested and modified according to user feedback over multiple cycles. The final version of the app was released in July 2019. Seventeen users aged 23 to 67 years evaluated the final version of the app using the SUS. The median (first, third quartile) SUS score for the app was 85 (68, 88) out of 100. The newly introduced functionalities were as follows: (1) capability to longitudinally track repeated fillings of the questionnaire at different time points by the same participant (as opposed to anonymous completion); (2) linking of the questionnaire with hemophilia registries, starting with the Canadian Bleeding Disorders Registry as a proof of concept; (3) removing or adding questions as needed; and (4) sending notifications to the users (eg, reminders). A new secure database was built for securely storing personal information separately from the questionnaire data. The PROBE online survey is currently available in 96 countries and 34 languages. The online survey was updated successfully, and the myPROBE app was developed, with a SUS score of 85 (out of 100). The app has been released in 81 countries and 34 languages. This will facilitate data collection for research and advocacy purposes, and the use of this tool in everyday clinical practice.

The research attempted to develop search filters for biomedical literature databases that improve retrieval of studies of clinical relevance for the nursing and rehabilitation professions. Diagnostic testing framework compared machine-culled and practitioner-nominated search terms with a hand-tagged clinical literature database. We were unable to: (1) develop filters for nursing, likely because of the overlapping and expanding scope of practice for nurses in comparison with medical professionals, or (2) develop filters for rehabilitation, because of its broad scope and the profession's multifaceted understanding of \"health and ability.\" We found limitations on search filter development for these health professions: nursing and rehabilitation.