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MDGAs (MAM domain-containing glycosylphosphatidylinositol anchors) are synaptic cell surface molecules that regulate the formation of trans-synaptic bridges between neurexins (NRXNs) and neuroligins (NLGNs), which promote synaptic development. Mutations in MDGAs are implicated in various neuropsychiatric diseases. MDGAs bind NLGNs in cis on the postsynaptic membrane and physically block NLGNs from binding to NRXNs. In crystal structures, the six immunoglobulin (Ig) and single fibronectin III domains of MDGA1 reveal a striking compact, triangular shape, both alone and in complex with NLGNs. Whether this unusual domain arrangement is required for biological function or other arrangements occur with different functional outcomes is unknown. Here, we show that WT MDGA1 can adopt both compact and extended 3D conformations that bind NLGN2. Designer mutants targeting strategic molecular elbows in MDGA1 alter the distribution of 3D conformations while leaving the binding affinity between soluble ectodomains of MDGA1 and NLGN2 intact. In contrast, in a cellular context, these mutants result in unique combinations of functional consequences, including altered binding to NLGN2, decreased capacity to conceal NLGN2 from NRXN1β, and/or suppressed NLGN2-mediated inhibitory presynaptic differentiation, despite the mutations being located far from the MDGA1-NLGN2 interaction site. Thus, the 3D conformation of the entire MDGA1 ectodomain appears critical for its function, and its NLGN-binding site on Ig1-Ig2 is not independent of the rest of the molecule. As a result, global 3D conformational changes to the MDGA1 ectodomain via strategic elbows may form a molecular mechanism to regulate MDGA1 action within the synaptic cleft.

Background: Cavernous carotid artery aneurysms can be treated by several endovascular techniques including flow diversion (FD) and parent vessel occlusion (PVO). We reviewed our institution's consecutive series of endovascularly treated cavernous carotid artery aneurysms to compare these two modalities and their associated clinical and radiographic outcomes. Methods: All patients harboring a cavernous carotid artery aneurysm treated by FD or PVO from January 2008 to December 2018 were enrolled. Data were collected retrospectively and analyzed on patient presentation, aneurysm dimensions, treatments and related complications, rate of aneurysm occlusion, sac regression, and outcomes. Results: Fourteen patients were treated with FD and 12 underwent PVO subsequent to passing a balloon test occlusion. There was no significant difference between treatment modalities in aneurysmal occlusion (97.0 ± 8.4% (FD) vs. 100% (PVO), p = 0.23), degree of sac regression (62.5 ± 16.7% (FD) vs. 56.8 ± 24.3% (PVO), p = 0.49), or near-complete to complete symptom improvement (66.7% (FD) vs. 81.8% (PVO), p = 0.62). Major complications included subarachnoid hemorrhage from aneurysmal rupture in 1 (7.1%) patient post-FD and 2 (16.7%) ischemic strokes following PVO. Conclusions: Endovascular treatment of cavernous carotid artery aneurysms by FD or PVO are both effective and safe. There is insufficient evidence to recommend one technique over the other and decision making should be individualized to the patient, their aneurysm morphology, and operator experience. [ABSTRACT FROM AUTHOR]

Background: Limited research exists regarding the impact of neuroimaging on endovascular thrombectomy (EVT) decisions for late-window cases of large vessel occlusion (LVO) stroke., Objective: T0 assess whether perfusion CT imaging: (1) alters the proportion of recommendations for EVT, and (2) enhances the reliability of EVT decision-making compared with non-contrast CT and CT angiography., Methods: We conducted a survey using 30 patients drawn from an institutional database of 3144 acute stroke cases. These were presented to 29 Canadian physicians with and without perfusion imaging. We used non-overlapping 95% confidence intervals and difference in agreement classification as criteria to suggest a difference between the Gwet AC1 statistics (κ G )., Results: The percentage of EVT recommendations differed by 1.1% with or without perfusion imaging. Individual decisions changed in 21.4% of cases (11.3% against EVT and 10.1% in favor). Inter-rater agreement (κ G ) among the 29 raters was similar between non-perfusion and perfusion CT neuroimaging (κ G =0.487; 95% CI 0.327 to 0.647 and κ G =0.552; 95% CI 0.430 to 0.675). The 95% CIs overlapped with moderate agreement in both. Intra-rater agreement exhibited overlapping 95% CIs for all 28 raters. κ G was either substantial or excellent (0.81-1) for 71.4% (20/28) of raters in both groups., Conclusions: Despite the minimal difference in overall EVT recommendations with either neuroimaging protocol one in five decisions changed with perfusion imaging. Regarding agreement we found that the use of automated CT perfusion images does not significantly impact the reliability of EVT decisions for patients with late-window LVO., Competing Interests: Competing interests: JWBD: Honoraria from Medtronic. Travel grant fromMicrovention; MAA: Member of the scientific advisory board of Palmera Medical;TRM: Principal of eVasc Neurovascular., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)