Collybolide Is a Novel Biased Agonist of κ-Opioid Receptors With Potent Antipruritic Activity

Among the opioid receptors, the κ-opioid receptor (κOR) has been gaining considerable attention as a potential therapeutic target for the treatment of complex CNS disorders including depression, visceral pain, and cocaine addiction. With an interest in discovering novel ligands targeting κOR, we searched natural products for unusual scaffolds and identified collybolide (Colly), a nonnitrogenous sesquiterpene from the mushroom Collybia maculata. This compound has a furyl-δ-lactone core similar to that of Salvinorin A (Sal A), another natural product from the plant Salvia divinorum. Characterization of the molecular pharmacological properties reveals that Colly, like Sal A, is a highly potent and selective κOR agonist. However, the two compounds differ in certain signaling and behavioral properties. Colly exhibits 10- to 50-fold higher potency in activating the mitogen-activated protein kinase pathway compared with Sal A. Taken with the fact that the two compounds are equipotent for inhibiting adenylyl cyclase activity, these results suggest that Colly behaves as a biased agonist of κOR. Behavioral studies also support the biased agonistic activity of Colly in that it exhibits ∼10-fold higher potency in blocking non–histamine-mediated itch compared with Sal A, and this difference is not seen in pain attenuation by these two compounds. These results represent a rare example of functional selectivity by two natural products that act on the same receptor. The biased agonistic activity, along with an easily modifiable structure compared with Sal A, makes Colly an ideal candidate for the development of novel therapeutics targeting κOR with reduced side effects

A Novel Ensemble Empirical Decomposition and Time–Frequency Analysis Approach for Vibroarthrographic Signal Processing

PurposePerson-centred physiotherapy in Intensive Care Units (ICU) supports patients’ early rehabilitation. Yet little is known about the activity required to enable person-centred physiotherapy in this setting. This study explores the experiences and interpretations of people who received physiotherapy.MethodsA qualitative study using Interpretative Phenomenological Analysis was conducted. Eight participants, recruited from a Ventilation Unit in Northwest England, were interviewed. Data were transcribed and managed using NVivo 12 software.ResultsParticipants described being “pushed” and guided by physiotherapists. The “emotional” pushing through motivation and encouragement, and “physical” pushing through setting goals, were perceived as person-centred activities, despite physiotherapists initially directing them. Other important aspects of individualised care were feeling safe and understanding how their body had changed.ConclusionsPatients viewed physiotherapist led rehabilitation in ICU as being person-centred, despite the lack of collaboration during early recovery, because they were too ill. Models of person-centred physiotherapy could be made more applicable to clinical settings by fully integrating the patient perspective

Deep phenotyping and genomic data from a nationally representative study on dementia in India

The Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD) is a nationally representative in-depth study of cognitive aging and dementia. We present a publicly available dataset of harmonized cognitive measures of 4,096 adults 60 years of age and older in India, collected across 18 states and union territories. Blood samples were obtained to carry out whole blood and serum-based assays. Results are included in a venous blood specimen datafile that can be linked to the Harmonized LASI-DAD dataset. A global screening array of 960 LASI-DAD respondents is also publicly available for download, in addition to neuroimaging data on 137 LASI-DAD participants. Altogether, these datasets provide comprehensive information on older adults in India that allow researchers to further understand risk factors associated with cognitive impairment and dementia.Peer reviewe