Notes

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Indications for flow diversion stent (FDS) treatment are expanding. However, there is still a lack of evidence for the long-term outcome in distally located aneurysms in the M2 segment of the middle cerebral artery (MCA) and beyond.

Consecutive subjects (from June 2013 to August 2020) with MCA aneurysms in the M2 segment or beyond treated with FDS were reviewed retrospectively. The primary endpoints for clinical safety were the absence of mortality, stroke event, re-rupture of the aneurysm, and worsening of clinical symptoms. The primary endpoint for treatment efficacy was complete/near-complete occlusion at follow-up after 12 months.

23 patients were identified 7 aneurysms were located in the M2 segment of the MCA, 4 in the M2-M3 bifurcation, 2 in M3, 3 in M3-4 branching, and 2 in M4; 5 aneurysms were located in M2 with extension into the M1-M2 bifurcation. 13 aneurysms were of fusiform morphology, 8 sacculofusiform, and 2 saccular. 16 aneurysms were of highly suspected dissecting etiology. The median diameter of the parent vessel was 2.1 mm proximally and 2 mm distally. The median time of the follow-up was 30 months (range 16 months to 6 years). Complete/near complete occlusion was observed in 14/20 patients (70%) and one stable remodeling (5%) was seen at 12 months. 22 patients (95.6%) had an excellent clinical outcome (mRS 0-1) at 6 months. Technical challenges associated with the deployment of FDS occurred in 8.7% of cases. Severe complications, intraparenchymal hemorrhage and re-rupture of the aneurysm occurred in 2 patients (8.7%).

Flow diversion of distally located aneurysms is technically feasible with low morbidity and mortality.
Flow diversion of distally located aneurysms is technically feasible with low morbidity and mortality.Precise control of the activity and abundance of ubiquitin-conjugating enzymes (E2s) ensures fidelity in ubiquitin chain synthesis. In this issue of Science Signaling, Liess et al. demonstrate that the human anaphase-promoting complex (APC/C)-associated E2 UBE2S adopts an autoinhibited dimeric state that increases the half-life of UBE2S by preventing its autoubiquitination-driven turnover.At the heart of protein ubiquitination cascades, ubiquitin-conjugating enzymes (E2s) form reactive ubiquitin-thioester intermediates to enable efficient transfer of ubiquitin to cellular substrates. The precise regulation of E2s is thus crucial for cellular homeostasis, and their deregulation is frequently associated with tumorigenesis. In addition to driving substrate ubiquitination together with ubiquitin ligases (E3s), many E2s can also autoubiquitinate, thereby promoting their own proteasomal turnover. To investigate the mechanisms that balance these disparate activities, we dissected the regulatory dynamics of UBE2S, a human APC/C-associated E2 that ensures the faithful ubiquitination of cell cycle regulators during mitosis. VE-821 ATR inhibitor We uncovered a dimeric state of UBE2S that confers autoinhibition by blocking a catalytically critical ubiquitin binding site. Dimerization is stimulated by the lysine-rich carboxyl-terminal extension of UBE2S that is also required for the recruitment of this E2 to the APC/C and is autoubiquitinated as substrate abundance becomes limiting. Consistent with this mechanism, we found that dimerization-deficient UBE2S turned over more rapidly in cells and did not promote mitotic slippage during prolonged drug-induced mitotic arrest. We propose that dimerization attenuates the autoubiquitination-induced turnover of UBE2S when the APC/C is not fully active. More broadly, our data illustrate how the use of mutually exclusive macromolecular interfaces enables modulation of both the activities and the abundance of E2s in cells to facilitate precise ubiquitin signaling.The high abundance of drug efflux pumps in cancer stem cells (CSCs) contributes to chemotherapy resistance. The transcriptional regulator SMAR1 suppresses CSC expansion in colorectal cancer, and increased abundance of SMAR1 is associated with better prognosis. Here, we found in breast tumors that the expression of SMAR1 was decreased in CSCs through the cooperative interaction of the pluripotency factors Oct4 and Sox2 with the histone deacetylase HDAC1. Overexpressing SMAR1 sensitized CSCs to chemotherapy through SMAR1-dependent recruitment of HDAC2 to the promoter of the gene encoding the drug efflux pump ABCG2. Treating cultured CSCs or 4T1 tumor-bearing mice with the nonsteroidal anti-inflammatory drug aspirin restored SMAR1 expression and ABCG2 repression and enhanced tumor sensitivity to doxorubicin. Our findings reveal transcriptional mechanisms regulating SMAR1 that also regulate cancer stemness and chemoresistance and suggest that, by restoring SMAR1 expression, aspirin might enhance chemotherapeutic efficacy in patients with stem-like tumors.Membrane trafficking processes regulate G protein-coupled receptor (GPCR) activity. Although class A GPCRs are capable of activating G proteins in a monomeric form, they can also potentially assemble into functional GPCR heteromers. Here, we showed that the class A serotonin 5-HT2A receptors (5-HT2ARs) affected the localization and trafficking of class C metabotropic glutamate receptor 2 (mGluR2) through a mechanism that required their assembly as heteromers in mammalian cells. In the absence of agonists, 5-HT2AR was primarily localized within intracellular compartments, and coexpression of 5-HT2AR with mGluR2 increased the intracellular distribution of the otherwise plasma membrane-localized mGluR2. Agonists for either 5-HT2AR or mGluR2 differentially affected trafficking through Rab5-positive endosomes in cells expressing each component of the 5-HT2AR-mGluR2 heterocomplex alone, or together. In addition, overnight pharmacological 5-HT2AR blockade with clozapine, but not with M100907, decreased mGluR2 density through a mechanism that involved heteromerization between 5-HT2AR and mGluR2. Using TAT-tagged peptides and chimeric constructs that are unable to form the interclass 5-HT2AR-mGluR2 complex, we demonstrated that heteromerization was necessary for the 5-HT2AR-dependent effects on mGluR2 subcellular distribution. The expression of 5-HT2AR also augmented intracellular localization of mGluR2 in mouse frontal cortex pyramidal neurons. Together, our data suggest that GPCR heteromerization may itself represent a mechanism of receptor trafficking and sorting.
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