Engagement in prevention services is crucial to reducing HIV risk among female entertainment and sex workers (FESW), and SMARTgirl is the national social marketing HIV prevention program for Cambodian women engaged in sex and entertainment work. Informed by the Behavioral Model of Vulnerable Populations, three multivariate logistic regression analyses examined correlates of three indices of engagement along the SMARTgirl HIV prevention continuum: (1) receipt of outreach services (past 3 months); (2) being registered as a SMARTgirl member; and (3) SMARTgirl club attendance (past year). Among the 1077 FESW enrolled in nine Cambodian provinces, women working in a brothel or freelance (adjusted odds ratio [aOR] 2.48; 95% CI 1.44-4.26) and those exchanging sex for drugs during the past 3 months (aOR 0.45; 95% CI 0.25-0.81) had significantly lower odds of contact with a SMARTgirl outreach worker. Women who reported having more than ten sexual partners in the past 3 months (aOR 0.54; 95% CI 0.32-0.89) and those who reported binge alcohol use (aOR 0.53; 95% CI 0.29-0.98) had significantly lower odds of being registered as SMARTgirl members. Exchanging sex for drugs was also associated with increased odds of attending a SMARTgirl club (aOR 2.03; 95% CI 1.04-3.98). Novel methods to deliver HIV prevention services are warranted to more effectively reach FESW who exchange sex for drugs, engage in binge alcohol use, report a greater number of sexual partners, and those not working in established work venues.

Class B G protein-coupled receptors (GPCRs) are notoriously difficult to target by small molecules because their large orthosteric peptide-binding pocket embedded deep within the transmembrane domain limits the identification and development of nonpeptide small molecule ligands. Using the parathyroid hormone type 1 receptor (PTHR) as a prototypic class B GPCR target, and a combination of molecular dynamics simulations and elastic network model-based methods, we demonstrate that PTHR druggability can be effectively addressed. Here we found a key mechanical site that modulates the collective dynamics of the receptor and used this ensemble of PTHR conformers to identify selective small molecules with strong negative allosteric and biased properties for PTHR signaling in cell and PTH actions in vivo. This study provides a computational pipeline to detect precise druggable sites and identify allosteric modulators of PTHR signaling that could be extended to GPCRs to expedite discoveries of small molecules as novel therapeutic candidates.

Purpose: To quantitatively investigate the microstructural properties of the optic nerve (ON) in vivo using diffusion magnetic resonance imaging (dMRI) tractography in an elderly population and to determine the differences between the ON diffusion properties stratified by basic demographics. Methods: We measured fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) of the intraorbital ON in cognitively normal controls selected from the Alzheimer's Disease Neuroimaging Initiative 3 database (n =104; mean age = 73. 8 ± 8.1 years) using dMRI probabilistic tractography and evaluated the correlation between diffusion parameters and demographic factors. Diffusion parameters were measured in 20 equidistant nodes along the tract, and the data from proximal 70% (14 nodes) of the intraorbital ON were averaged. Results: The mean FA of the intraorbital ON was 0.392 ± 0.063, and the mean MD was 1.163 ± 0.165 μm²/s. The mean RD was 0.882 ± 0.152 μm²/s, and the mean AD was 1.693 ± 0.183 μm²/s. The multiple linear regression model showed a negative correlation between FA and age. FA in females was significantly higher than males, whereas RD in female was significantly lower. Conclusions: We measured the diffusion properties of the intraorbital ON using dMRI tractography in an elderly cognitively normal population. The diffusion properties detected by dMRI tractography may substantially reflect the microstructure of the ON.

The parathyroid hormone (PTH) type 1 receptor (PTHR) is a class B G protein–coupled receptor (GPCR) that regulates mineral ion, vitamin D, and bone homeostasis. Activation of the PTHR by PTH induces both transient cell surface and sustained endosomal cAMP production. To address whether the spatial (location) or temporal (duration) dimension of PTHR-induced cAMP encodes distinct biological outcomes, we engineered a biased PTHR ligand (PTH^7d) that elicits cAMP production at the plasma membrane but not at endosomes. PTH^7d stabilized a unique active PTHR conformation that mediated sustained cAMP signaling at the plasma membrane due to impaired β-arrestin coupling to the receptor. Experiments in cells and mice revealed that sustained cAMP production by cell surface PTHR failed to mimic the pharmacological effects of sustained endosomal cAMP production on the abundance of the rate-limiting hydroxylase catalyzing the formation of active vitamin D, as well as increases in circulating active vitamin D and Ca²⁺ and in bone formation in mice. Thus, similar amounts of cAMP generated by PTHR for similar lengths of time in different cellular locations, plasma membrane and endosomes, mediate distinct physiological responses. These results unveil subcellular signaling location as a means to achieve specificity in PTHR-mediated biological outcomes and raise the prospect of rational drug design based upon spatiotemporal manipulation of GPCR signaling.

The incidence of metabolic and chronic diseases including cancer, obesity, inflammation-related diseases sharply increased in the 21st century. Major underlying causes for these diseases are inflammation and oxidative stress. Accordingly, natural products and their bioactive components are obvious therapeutic agents for these diseases, given their antioxidant and anti-inflammatory properties. Research in this area has been significantly expanded to include chemical identification of these compounds using advanced analytical techniques, determining their mechanism of action, food fortification and supplement development, and enhancing their bioavailability and bioactivity using nanotechnology. These timely topics were discussed at the 20th Frontier Scientists Workshop sponsored by the Korean Academy of Science and Technology, held at the University of Hawaii at Manoa on 23 November 2019. Scientists from South Korea and the U.S. shared their recent research under the overarching theme of Bioactive Compounds, Nanoparticles, and Disease Prevention. This review summarizes presentations at the workshop to provide current knowledge of the role of natural products in the prevention and treatment of metabolic diseases.