Endothelial cell (EC) activation is an early hallmark in the pathogenesis of chronic vascular diseases. MicroRNA-181b (Mir181b) is an important anti-inflammatory mediator in the vascular endothelium affecting endotoxemia, atherosclerosis, and insulin resistance. Herein, we identify that the drug methotrexate (MTX) and its downstream metabolite adenosine exert anti-inflammatory effects in the vascular endothelium by targeting and activating Mir181b expression. Both systemic and endothelial-specific Mir181a2b2-deficient mice develop vascular inflammation, white adipose tissue (WAT) inflammation, and insulin resistance in a diet-induced obesity model. Moreover, MTX attenuated diet-induced WAT inflammation, insulin resistance, and EC activation in a Mir181a2b2-dependent manner. Mechanistically, MTX attenuated cytokine-induced EC activation through a unique adenosine-adenosine receptor A3-SMAD3/4-Mir181b signaling cascade. These findings establish an essential role of endothelial Mir181b in controlling vascular inflammation and that restoring Mir181b in ECs by high-dose MTX or adenosine signaling may provide a potential therapeutic opportunity for anti-inflammatory therapy.

Science is undergoing rapid change with the movement to improve science focused largely on reproducibility/replicability and open science practices. This moment of change-in which science turns inward to examine its methods and practices-provides an opportunity to address its historic lack of diversity and noninclusive culture. Through network modeling and semantic analysis, we provide an initial exploration of the structure, cultural frames, and women's participation in the open science and reproducibility literatures (n = 2,926 articles and conference proceedings). Network analyses suggest that the open science and reproducibility literatures are emerging relatively independently of each other, sharing few common papers or authors. We next examine whether the literatures differentially incorporate collaborative, prosocial ideals that are known to engage members of underrepresented groups more than independent, winner-takes-all approaches. We find that open science has a more connected, collaborative structure than does reproducibility. Semantic analyses of paper abstracts reveal that these literatures have adopted different cultural frames: open science includes more explicitly communal and prosocial language than does reproducibility. Finally, consistent with literature suggesting the diversity benefits of communal and prosocial purposes, we find that women publish more frequently in high-status author positions (first or last) within open science (vs. reproducibility). Furthermore, this finding is further patterned by team size and time. Women are more represented in larger teams within reproducibility, and women's participation is increasing in open science over time and decreasing in reproducibility. We conclude with actionable suggestions for cultivating a more prosocial and diverse culture of science.

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.