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Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions-both therapeutic and hallucinogenic-are not understood, although activation of the 5-HT2A serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH-a prototypical hallucinogen-in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders.

The objective of this study was to investigate changes in physical activity patterns associated with the COVID-19 pandemic in individuals with overweight and obesity who were participating in a school district worksite weight loss program. We conducted comparative design interrupted time series analyses on physical activity device (Fitbit) data from the 2018-2019 and 2019-2020 school years (N = 211). We administered a questionnaire in 2020 to supplement device data. After the stay-at-home orders in 2020, participants tended to decrease their weekly step count (B = -1315.7, SE = 627.7, p = .045), decrease their weekly 'Lightly active minutes' (B = -39.1, SE = 12.6, p = .007), and increase their weekly 'Very active minutes' compared to their counterparts from the year before (B = 7.6, SE = 3.2, p = .020). Decreased motivation, gym closures, and safety concerns were cited as barriers to physical activity. Having more time and health consciousness were cited as facilitators of physical activity. The COVID-19 pandemic was related to changes in physical activity in both positive and negative ways, revealing opportunities to promote healthy lifestyle behaviors in this population. More research is needed to determine optimal approaches to health promotion in the post-COVID-19 era., Author(s): Michael C. Robertson [sup.1] [sup.2] , Che Young Lee [sup.1] , Ivan Haw-Chong Wu [sup.3] , Yue Liao [sup.4] , Margaret Raber [sup.1] [sup.5] , Nathan Parker [sup.6] , [...]

Background: There is a need to understand how schools adopt physical activity approaches (curricula, programs and practices), but few studies report on this process. Purpose: To obtain elementary school staff's perspectives regarding how their schools are currently adopting physical activity approaches. Methods: We recruited 15 participants from four job types in an urban Texas school district to participate in semi-structured interviews. We coded and analyzed interviews using directed content analysis and iterative categorization. Results: We identified four themes pertaining to how the district, schools, and teachers contribute to the adoption of approaches. Themes included: (1) Staff identify new approaches through numerous channels; (2) Adoption occurs at multiple organizational levels; (3) District staff fulfilled a supporting role in the adoption process; and (4) School staff's perceptions of approach characteristics influence adoption. Discussion: We found that schools adopt physical activity approaches at both the district- and school-level. Additionally, multiple stakeholders played a role in the adoption process and those roles varied across approaches. Translation to Health Education Practice: Time, money, space, staff, competing priorities, limited information, the school's mission, and the benefits an approach provides to children are factors that researchers and practitioners should consider when starting a new physical activity approach.

Background: Rural cancer survivors face a greater number of health disparities, including poorer health-related quality of life (HRQoL), than urban cancer survivors. Engagement in healthy lifestyle behaviors also varies between rural and urban cancer survivors. Lifestyle behaviors can improve HRQoL; however, the combination of behaviors most important for HRQoL in rural survivors is unclear. This study examined clusters of lifestyle behaviors in rural cancer survivors, and differences in HRQoL between behavioral clusters. Methods: Rural cancer survivors in the United States (N = 219) completed a cross-sectional survey. Lifestyle behaviors were classified into unhealthy/healthy binary categories (inactive/active, longer/shorter sedentary time, excessive/acceptable fat intake, very low/higher fruit and vegetable intake, some/no alcohol consumption, and poor/good sleep quality). Behavioral clusters were identified by latent class analysis. HRQoL differences between behavioral clusters were assessed by ordinary least squares regression. Results: The 2-class model demonstrated the best fit and interpretability. The "mostly unhealthy behaviors" class (38.5% of sample) had higher probabilities of all unhealthy behaviors, except alcohol consumption. The "healthier energy balance" class (61.5% of sample) had higher probabilities of active, shorter sedentary, higher fruit and vegetable consumption, excessive fat intake, some alcohol consumption, and poor sleep categories, and reported better HRQoL. Conclusions: Healthier energy balance behaviors were particularly relevant for HRQoL in rural cancer survivors. Multiple behavior change interventions to improve HRQoL in rural cancer survivors should focus on supporting energy balance behaviors. Many rural cancer survivors may lead very unhealthy lifestyles, placing them at high risk of adverse outcomes. This subpopulation should be prioritized to help alleviate cancer health disparities. [ABSTRACT FROM AUTHOR]

The calcium-sensing receptor (CaSR), a cell-surface sensor for Ca.sup.2+, is the master regulator of calcium homeostasis in humans and is the target of calcimimetic drugs for the treatment of parathyroid disorders.sup.1. CaSR is a family C G-protein-coupled receptor.sup.2 that functions as an obligate homodimer, with each protomer composed of a Ca.sup.2+-binding extracellular domain and a seven-transmembrane-helix domain (7TM) that activates heterotrimeric G proteins. Here we present cryo-electron microscopy structures of near-full-length human CaSR in inactive or active states bound to Ca.sup.2+ and various calcilytic or calcimimetic drug molecules. We show that, upon activation, the CaSR homodimer adopts an asymmetric 7TM configuration that primes one protomer for G-protein coupling. This asymmetry is stabilized by 7TM-targeting calcimimetic drugs adopting distinctly different poses in the two protomers, whereas the binding of a calcilytic drug locks CaSR 7TMs in an inactive symmetric configuration. These results provide a detailed structural framework for CaSR activation and the rational design of therapeutics targeting this receptor. Cryo-EM structures of human calcium-sensing receptor reveal intrinsic asymmetry in the receptor homodimer upon activation that is stabilized by calcimimetic drugs adopting distinct poses in the two protomers, priming one protomer for G-protein coupling., Author(s): Yang Gao [sup.1] [sup.2] , Michael J. Robertson [sup.1] [sup.2] , Sabrina N. Rahman [sup.4] , Alpay B. Seven [sup.1] [sup.2] , Chensong Zhang [sup.1] [sup.2] , Justin G. [...]

Family C G-protein-coupled receptors (GPCRs) operate as obligate dimers with extracellular domains that recognize small ligands, leading to G-protein activation on the transmembrane (TM) domains of these receptors by an unknown mechanism.sup.1. Here we show structures of homodimers of the family C metabotropic glutamate receptor 2 (mGlu2) in distinct functional states and in complex with heterotrimeric G.sub.i. Upon activation of the extracellular domain, the two transmembrane domains undergo extensive rearrangement in relative orientation to establish an asymmetric TM6-TM6 interface that promotes conformational changes in the cytoplasmic domain of one protomer. Nucleotide-bound G.sub.i can be observed pre-coupled to inactive mGlu2, but its transition to the nucleotide-free form seems to depend on establishing the active-state TM6-TM6 interface. In contrast to family A and B GPCRs, G-protein coupling does not involve the cytoplasmic opening of TM6 but is facilitated through the coordination of intracellular loops 2 and 3, as well as a critical contribution from the C terminus of the receptor. The findings highlight the synergy of global and local conformational transitions to facilitate a new mode of G-protein activation. Cryo-electron microscopy structures show that metabotropic glutamate receptor 2 forms a dimer to which only one G protein is coupled, revealing the basis for asymmetric signal transduction., Author(s): Alpay B. Seven [sup.1] , Ximena Barros-Álvarez [sup.1] , Marine de Lapeyrière [sup.2] , Makaía M. Papasergi-Scott [sup.1] , Michael J. Robertson [sup.1] , Chensong Zhang [sup.1] , Robert [...]