Late-stage installation and functionalization of alkyl pyridiniums: a general HTE amenable strategy to access diverse aryl alanine containing macrocyclic peptides.

This manuscript describes a strategy to readily access diverse aryl and homoaryl alanine-containing pharmaceutically relevant macrocyclic peptides. A two-step sequence involving the late-stage installation of the pyridinium functionality on macrocyclic peptides followed by reductive couplings was implemented. These transformations are amenable to microscale high-throughput experimentation (HTE) and enable rapid access to aryl alanine-containing macrocyclic peptides that would otherwise be inaccessible solid-phase peptide synthesis using commercially available amino acids.

Backbone Modification Provides a Long-Acting Inverse Agonist of Pathogenic, Constitutively Active PTH1R Variants.

Parathyroid hormone 1 receptor (PTH1R) plays a key role in mediating calcium homeostasis and bone development, and aberrant PTH1R activity underlies several human diseases. Peptidic PTH1R antagonists and inverse agonists have therapeutic potential in treating these diseases, but their poor pharmacokinetics and pharmacodynamics undermine their in vivo efficacy. Herein, we report the use of a backbone-modification strategy to design a peptidic PTH1R inhibitor that displays prolonged activity as an antagonist of wild-type PTH1R and an inverse agonist of the constitutively active PTH1R-H223R mutant both in vitro and in vivo.

Radial glia promote microglial development through integrin αβ -TGFβ1 signaling.

Microglia diversity emerges from interactions between intrinsic genetic programs and environment-derived signals, but how these processes unfold and interact in the developing brain remains unclear. Here, we show that radial glia-expressed integrin beta 8 (ITGB8) expressed in radial glia progenitors activates microglia-expressed TGFβ1, permitting microglial development. Domain-restricted deletion of in these progenitors establishes complementary regions with developmentally arrested "dysmature" microglia that persist into adulthood.

Hormone Analogues with Unique Signaling Profiles from Replacement of α-Residue Triads with β/γ Diads.

We have applied an underexplored backbone modification strategy to generate new analogues of peptides that activate two clinically important class B1 G protein-coupled receptors (GPCRs). Most peptide modification strategies involve changing side chains or, less commonly, changing the configuration at side chain-bearing carbons (i.e.

'Oh, I don't really want to bother with that:' gay and bisexual young men's perceptions of barriers to PrEP information and uptake.

Pre-exposure prophylaxis (PrEP), a daily oral pill for HIV prevention demonstrated to be effective for adults, was recently approved by the US Food and Drug Administration for use with young people weighing at least 35 kilograms. Given that young people aged 13-19 years account for a disproportionate share of new US HIV infections, PrEP presents an important opportunity. There has been limited effort, however, to increase PrEP awareness and uptake among young people.

Sleep, waking and sleep inertia in sexual assault: A retrospective descriptive study.

Women who wake from sleep during sexual assault commonly report confusion and disorientation. Confusion and disorientation, with impaired decision making after waking, are symptoms of 'sleep inertia', and part of the normal transition from sleep to full wakefulness which is maximal in the minutes after wakening and can be prolonged. In this study of 305 adult females (median age 26, range 18-68), who presented for a sexual assault forensic medical examination, 38 (12%) (median age 27, range 18-51) woke to find sexual acts already in progress.