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A massive intronic hexanucleotide repeat (GGGGCC) expansion in C9ORF72 is a genetic origin of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recently, C9ORF72, together with SMCR8 and WDR41, has been shown to regulate autophagy and function as Rab GEF. However, the precise function of C9ORF72 remains unclear. Here, we report the cryogenic electron microscopy (cryo-EM) structure of the human C9ORF72–SMCR8–WDR41 complex at a resolution of 3.2 Å. The structure reveals the dimeric assembly of a heterotrimer of C9ORF72–SMCR8–WDR41. Notably, the C-terminal tail of C9ORF72 and the DENN domain of SMCR8 play critical roles in the dimerization of the two protomers of the C9ORF72–SMCR8–WDR41 complex. In the protomer, C9ORF72 and WDR41 are joined by SMCR8 without direct interaction. WDR41 binds to the DENN domain of SMCR8 by the C-terminal helix. Interestingly, the prominent structural feature of C9ORF72–SMCR8 resembles that of the FLNC–FNIP2 complex, the GTPase activating protein (GAP) of RagC/D. Structural comparison and sequence alignment revealed that Arg147 of SMCR8 is conserved and corresponds to the arginine finger of FLCN, and biochemical analysis indicated that the Arg147 of SMCR8 is critical to the stimulatory effect of the C9ORF72–SMCR8 complex on Rab8a and Rab11a. Our study not only illustrates the basis of C9ORF72–SMCR8–WDR41 complex assembly but also reveals the GAP activity of the C9ORF72–SMCR8 complex.

Researchers interested in mathematical proficiency have recently begun to explore the development of strategic flexibility, where flexibility is defined as knowledge of multiple strategies for solving a problem and the ability to implement an innovative strategy for a given problem solving circumstance. However, anecdotal findings from this literature indicate that students do not consistently use an innovative strategy for solving a given problem, even when these same students demonstrate knowledge of innovative strategies. This distinction, sometimes framed in the psychological literature as competence vs. performance—has not been previously studied for flexibility. In order to explore the competence/performance distinction in flexibility, this study developed and validated measures for potential flexibility (e.g., competence, or knowledge of multiple strategies) and practical flexibility (e.g., performance, use of innovative strategies) for solving equations. The measures were administrated to a sample of 158 Chinese middle school students through a Tri-Phase Flexibility Assessment, in which the students were asked to solve each equation, generate additional strategies, and evaluate own multiple strategies. Confirmatory factor analysis supported a two-factor model of potential and practical flexibility. Satisfactory internal consistency was found for the measures. Additional validity evidence included the significant association with flexibility measured with the previous method. Potential flexibility and practical flexibility were found to be distinct but related. The theoretical and practical implications of the concepts and their measures of potential flexibility and practical flexibility are discussed.

HTN, rather than fever, is the leading reason for patients with Takayasu arteritis to see a doctor in China. HTN, major complications, and a progressive disease course are statistically significant predictors of survival. Because of cardiovascular events associated with the disease, early diagnosis and treatment are urgent to improve prognosis.