Structural and Mechanistic Regulation of the Pro-degenerative NAD Hydrolase SARM1.

The NADase SARM1 is a central switch in injury-activated axon degeneration, an early hallmark of many neurological diseases. Here, we present cryo-electron microscopy (cryo-EM) structures of autoinhibited (3.3 Å) and active SARM1 (6.8 Å) and provide mechanistic insight into the tight regulation of SARM1's function by the local metabolic environment. Although both states retain an octameric core, the defining feature of the autoinhibited state is a lock between the autoinhibitory Armadillo/HEAT motif (ARM) and catalytic Toll/interleukin-1 receptor (TIR) domains, which traps SARM1 in an inactive state. Mutations that break this lock activate SARM1, resulting in catastrophic neuronal death. Notably, the mutants cannot be further activated by the endogenous activator nicotinamide mononucleotide (NMN), and active SARM1 is product inhibited by Nicotinamide (NAM), highlighting SARM1's functional dependence on key metabolites in the NAD salvage pathway. Our studies provide a molecular understanding of SARM1's transition from an autoinhibited to an injury-activated state and lay the foundation for future SARM1-based therapies to treat axonopathies.

Vitrectomy alone in the management of giant retinal tears.

BACKGROUND AND OBJECTIVE: To evaluate the outcomes of vitrectomy without adjuvant scleral buckling for giant retinal tear (GRT) detachment and assess the impact of preoperative lens status on these outcomes. PATIENTS AND METHODS: Retrospective review of consecutive cases of vitrectomy alone for primary GRT detachment at the University of Michigan from October 1992 through October 2012. The primary outcome measure was Kaplan-Meier­estimated single-surgery reattachment rate at 3 months. RESULTS: Eligibility criteria were met by 41 eyes of 40 patients. Six eyes (15%) had grade C proliferative vitreoretinopathy at baseline. The single-surgery reattachment rate was 83% (95% CI: 67%, 91%) at 3 months, with no significant difference between phakic and nonphakic eyes. CONCLUSION: Based on this retrospective series, and within the confines of our eligibility criteria, adjuvant scleral buckling does not appear to be necessary in the management of primary GRT detachment.

Bromine-catalyzed conversion of CO2 and epoxides to cyclic carbonates under continuous flow conditions.

A continuous method for the formation of cyclic carbonates from epoxides and carbon dioxide (CO2) is described. The catalysts used are inexpensive and effective in converting the reagents to the products in a residence time (t(R)) of 30 min. The cyclic carbonate products are obtained in good to excellent yield (51-92%). On the basis of a series of kinetics experiments, we propose a reaction mechanism involving epoxide activation by electrophilic bromine and CO2 activation by an amide.

Gold(I)-catalyzed intramolecular tandem addition/Friedel-Crafts reactions between acyclic enamides and 1-arylalkynes.

Electron-deficient acyclic enamine derivatives react with electron-rich 1-arylalkynes using cationic gold(I) species as catalysts in an intramolecular process to form annulated 1-amido-substituted indene derivatives as the major products. Yields for this process range between 21% and 98%. In some cases, a two-step process that includes a subsequent alkene isomerization is needed.

Enamides and enesulfonamides as nucleophiles: formation of complex ring systems through a platinum(II)-catalyzed addition/Friedel-Crafts pathway.

Cyclic enamine derivatives (enesulfonamides and enamides) tethered to an 1-arylalkynyl fragment undergo a platinum(II)-catalyzed tandem alkyne addition/Friedel-Crafts ring closure to form nitrogen-containing polycyclic structures. Regioselectivity in the initial addition of the enesulfonamide or enamide nucleophile to the platinum(II)-alkyne complex is important. Electron-rich arenes and heterocycles led to the formation of products resulting from an initial 6-endo cyclization. Twenty-three examples of this process are presented.

Pyrrole synthesis catalyzed by AgOTf or cationic Au(I) complexes.

Either silver trifluoromethanesulfonate or a mixture of gold(I) chloride, silver trifluoromethanesulfonate, and triphenylphosphine catalyze the formation of pyrroles from substituted beta-alkynyl ketones and amines. The reactions proceed by using 5 mol % of catalyst with yields of isolated pyrroles ranging from 13% to 92%. Sixteen examples are used to compare the effectiveness of each catalyst.