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. This peptide may be of interest for the future development of therapeutic agents that ameliorate PTH1R malfunction.

Radial glia promote microglial development through integrin αVß8 -TGFß1 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 TGFß1, permitting microglial development. Domain-restricted deletion of Itgb8 in these progenitors establishes complementary regions with developmentally arrested "dysmature" microglia that persist into adulthood. In the absence of autocrine TGFß1 signaling, we find that microglia adopt a similar dysmature phenotype, leading to neuromotor symptoms almost identical to Itgb8 mutant mice. In contrast, microglia lacking the TGFß signal transducers Smad2 and Smad3 have a less polarized dysmature phenotype and correspondingly less severe neuromotor dysfunction. Finally, we show that non-canonical (Smad-independent) signaling partially suppresses disease and development associated gene expression, providing compelling evidence for the adoption of microglial developmental signaling pathways in the context of injury or disease.

Hormone Analogues with Unique Signaling Profiles from Replacement of α-Residue Triads with ß/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., l residues replaced by d residues). In contrast, backbone modifications alter the number of backbone atoms and the identities of backbone atoms relative to a poly-α-amino acid backbone. Starting from the peptide agonists PTH(1-34) (the first 34 residues of the parathyroid hormone, used clinically as the drug teriparatide) and glucagon-like peptide-1 (7-36) (GLP-1(7-36)), we replaced native α-residue triads with a diad composed of a ß-amino acid residue and a γ-amino acid residue. The ß/γ diad retains the number of backbone atoms in the ααα triad. Because the ß and γ residue each bear a single side chain, we implemented ααα→ßγ replacements at sites that contained a Gly residue (i.e., at α-residue triads that presented only two side chains). All seven of the α/ß/γ-peptides derived from PTH(1-34) or GLP-1(7-36) bind to the cognate receptor (the PTHR1 or the GLP-1R), but they vary considerably in their activity profiles. Outcomes include functional mimicry of the all-α agonist, receptor-selective agonist activity, biased agonism, or strong binding with weak activation, which could lead to antagonist development. Collectively, these findings demonstrate that ααα→ßγ replacements, which are easily implemented via solid-phase synthesis, can generate peptide hormone analogues that display unique and potentially useful signaling behavior.

'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. While prior work has identified barriers young people face in getting PrEP, effective strategies for overcoming these barriers have not yet been identified. This paper presents results from interviews with 15-19 year old gay and bisexual young men about their knowledge and perceptions of PrEP, and the barriers they perceive. Results suggest that participants were aware of PrEP but confused by the details of insurance coverage and out-of-pocket costs. Participants also felt parents and providers would not be knowledgeable or supportive, and were reluctant to share their own use of PrEP on social media. Suggested next steps include online parent and provider education, systemic health care reform to streamline and simplify access to preventative care and awareness campaigns that meet youth where they are on popular platforms.

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. For 25 of these women (25/38 for 66%), an act of penile-vaginal penetration was already occurring when the woman woke. Of the 38 women (12%) who woke during the sexual assault, several had factors known to enhance the impairment of sleep inertia including forced arousal (38/38, 100%) and age under 25 (15/38, 39%). 17 (17/38 for 45%) of these women who woke had consumed varying amounts of alcohol prior to sleep and these 17 woke fully during the assault and then stayed awake. A further 16 women, (16/38 for 42%) woke during the sexual assault but returned to sleep during or after the assault, and all these 16 gave a history of intoxication by drugs or alcohol prior to sleep. Importantly 5, (5/38 for 13%) of the women who woke during the assault had consumed no intoxicating substances. A further 68 (23%) of the 305 women, (median age 26, range 18-58) had no memory on waking of the alleged sexual assault despite having other reasons to believe that a sexual assault had occurred. Forensic medical examiners can assist both the justice process, and patient care, by considering the possibility of sleep inertia among victims who report disorientation and slow or confused decision making on waking during a sexual assault.