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BackgroundPhysical activity can confer diverse benefits on cancer survivors. Unfortunately, many cancer survivors are not sufficiently active. The efficacy of physical activity interventions for this population may be increased by grounding them in Self-Determination Theory (SDT). Combining game design elements with wearable technologies may be a useful and scalable approach to targeting SDT constructs to promote cancer survivors’ physical activity. ObjectiveThe primary aim of this study is to evaluate the feasibility and acceptability of Steps2Health, a physical activity intervention for cancer survivors. It also aims to investigate the effects of the intervention on motivation, physical activity, and step count. MethodsWe randomized 78 insufficiently active cancer survivors to an experimental or comparison group. All participants received a physical activity tracker. The experimental group participants also received a set sequence of multimedia messaging service messages that were triggered in real time by meeting predetermined cumulative step count totals. Messages presented information about a virtual journey and included photographs and vivid descriptions of locations to increase autonomous motivation. Additional messages targeted perceptions of relatedness (eg, role modeling) and competence (eg, facilitating mastery experiences). We administered pre- and postintervention surveys and conducted 15 individual interviews to evaluate the intervention. We performed directed content analysis of qualitative data and conducted mixed effects linear modeling to investigate participants’ changes in motivation, self-reported physical activity, and device-measured step counts. ResultsThere was minimal loss to follow-up (3/78, 4%), the device wear rate was high (2548/3044, 83.71% of days), and technical problems with messaging based on real-time step counts were limited. Our qualitative data analysis revealed 3 overarching themes: accessibility, autonomous motivation, and relatedness. Participants successfully navigated the technological aspects and game design elements of the intervention. Participants found messages targeting autonomous motivation and competence or self-efficacy to be enjoyable and compelling, but one feasibility criterion for participant engagement (response rate to text messages) was not met. Messages targeting relatedness were less highly rated than the messages targeting autonomous motivation and competence or self-efficacy. During the intervention, both groups increased their motivation for physical activity (B=0.16; 95% CI 0.01 to 0.30; P=.04; d=0.49), and assignment to the experimental group was associated with increased self-reported leisure activity score (B=10.78; 95% CI 3.54 to 18.02; P=.005; d=0.64). The experimental group had greater increases in daily step counts over time (B=322.08; 95% CI 54.01 to 590.15; P=.02; d=0.28). ConclusionsThis study supports the feasibility of using real-time game design elements to target SDT constructs and increase cancer survivors’ physical activity. Overall, our findings support the acceptability of the Steps2Health intervention, but fostering active participant engagement and targeting relatedness may present additional challenges. Steps2Health may help cancer survivors increase their physical activity levels.

BackgroundCancer survivors are at an elevated risk for several negative health outcomes, but physical activity (PA) can decrease those risks. Unfortunately, adherence to PA recommendations among survivors is low. Fitness mobile apps have been shown to facilitate the adoption of PA in the general population, but there are limited apps specifically designed for cancer survivors. This population has unique needs and barriers to PA, and most existing PA apps do not address these issues. Moreover, incorporating user preferences has been identified as an important priority for technology-based PA interventions, but at present there is limited literature that serves to establish these preferences in cancer survivors. This is especially problematic given the high cost of app development and because the majority of downloaded apps fail to engage users over the long term. ObjectiveThe aim of this study was to take a qualitative approach to provide practical insight regarding this population’s preferences for the features and messages of an app to increase PA. MethodsA total of 35 cancer survivors each attended 2 focus groups; a moderator presented slide shows on potential app features and messages and asked open-ended questions to elicit participant preferences. All sessions were audio recorded and transcribed verbatim. Three reviewers independently conducted thematic content analysis on all transcripts, then organized and consolidated findings to identify salient themes. ResultsParticipants (mean age 63.7, SD 10.8, years) were mostly female (24/35, 69%) and mostly white (25/35, 71%). Participants generally had access to technology and were receptive to engaging with an app to increase PA. Themes identified included preferences for (1) a casual, concise, and positive tone, (2) tools for personal goal attainment, (3) a prescription for PA, and (4) an experience that is tailored to the user. Participants reported wanting extensive background data collection with low data entry burden and to have a trustworthy source translate their personal data into individualized PA recommendations. They expressed a desire for app functions that could facilitate goal achievement and articulated a preference for a more private social experience. Finally, results indicated that PA goals might be best established in the context of personally held priorities and values. ConclusionsMany of the desired features identified are compatible with both empirically supported methods of behavior change and the relative strengths of an app as a delivery vehicle for behavioral intervention. Participating cancer survivors’ preferences contrasted with many current standard practices for mobile app development, including value-based rather than numeric goals, private socialization in small groups rather than sharing with broader social networks, and interpretation of PA data rather than merely providing numerical data. Taken together, these insights may help increase the acceptability of theory-based mHealth PA interventions in cancer survivors.

There is considerable interest in screening ultralarge chemical libraries for ligand discovery, both empirically and computationally1-4. Efforts have focused on readily synthesizable molecules, inevitably leaving many chemotypes unexplored. Here we investigate structure-based docking of a bespoke virtual library of tetrahydropyridines-a scaffold that is poorly sampled by a general billion-molecule virtual library but is well suited to many aminergic G-protein-coupled receptors. Using three inputs, each with diverse available derivatives, a one pot C-H alkenylation, electrocyclization and reduction provides the tetrahydropyridine core with up to six sites of derivatization5-7. Docking a virtual library of 75 million tetrahydropyridines against a model of the serotonin 5-HT2A receptor (5-HT2AR) led to the synthesis and testing of 17 initial molecules. Four of these molecules had low-micromolar activities against either the 5-HT2A or the 5-HT2B receptors. Structure-based optimization led to the 5-HT2AR agonists (R)-69 and (R)-70, with half-maximal effective concentration values of 41 nM and 110 nM, respectively, and unusual signalling kinetics that differ from psychedelic 5-HT2AR agonists. Cryo-electron microscopy structural analysis confirmed the predicted binding mode to 5-HT2AR. The favourable physical properties of these new agonists conferred high brain permeability, enabling mouse behavioural assays. Notably, neither had psychedelic activity, in contrast to classic 5-HT2AR agonists, whereas both had potent antidepressant activity in mouse models and had the same efficacy as antidepressants such as fluoxetine at as low as 1/40th of the dose. Prospects for using bespoke virtual libraries to sample pharmacologically relevant chemical space will be considered.

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] , [...]

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 [...]