Identification of a binding site for small molecule inhibitors targeting human TRPM4.

Transient receptor potential (TRP) melastatin 4 (TRPM4) protein is a calcium-activated monovalent cation channel associated with various genetic and cardiovascular disorders. The anthranilic acid derivative NBA is a potent and specific TRPM4 inhibitor, but its binding site in TRPM4 has been unknown, although this information is crucial for drug development targeting TRPM4. We determine three cryo-EM structures of full-length human TRPM4 embedded in native lipid nanodiscs without inhibitor, bound to NBA, and an anthranilic acid derivative, IBA.

Gastrointestinal tolerability and weight reduction associated with tirzepatide in adults with obesity or overweight with and without type 2 diabetes in the SURMOUNT-1 to -4 trials.

Aims: This analysis evaluated whether gastrointestinal (GI) adverse events (AEs) including nausea, vomiting, diarrhoea (N/V/D) and dyspepsia were associated with weight reduction with tirzepatide across the SURMOUNT-1 to -4 trials.

Materials And Methods: SURMOUNT-1 to -4 were global Phase 3 clinical trials evaluating the safety and efficacy of tirzepatide among participants with obesity or overweight with or without type 2 diabetes (T2D). Participants were randomly assigned to receive once weekly subcutaneous tirzepatide or placebo.

Posterior Shoulder Stability Depends on Acromial Anatomy: A Cadaveric, Biomechanical Study.

Background: Failure rates in the management of recurrent posterior shoulder instability remain a concern. Cadaveric studies have established that posterior capsulolabral tears, glenoid retroversion, and posterior glenoid bone loss result in increased posterior humeral head translation in the setting of a posteriorly directed force. A high and flat acromion has recently been associated with posterior instability.

Search for Soft Unclustered Energy Patterns in Proton-Proton Collisions at 13 TeV.

The first search for soft unclustered energy patterns (SUEPs) is performed using an integrated luminosity of 138  fb^{-1} of proton-proton collision data at sqrt[s]=13  TeV, collected in 2016-2018 by the CMS detector at the LHC. Such SUEPs are predicted by hidden valley models with a new, confining force with a large 't Hooft coupling. In events with boosted topologies, selected by high-threshold hadronic triggers, the multiplicity and sphericity of clustered tracks are used to reject the background from standard model quantum chromodynamics.