Crystal structure of the GLP-1 receptor bound to a peptide agonist.

Glucagon-like peptide 1 (GLP-1) regulates glucose homeostasis through the control of insulin release from the pancreas. GLP-1 peptide agonists are efficacious drugs for the treatment of diabetes. To gain insight into the molecular mechanism of action of GLP-1 peptides, here we report the crystal structure of the full-length GLP-1 receptor bound to a truncated peptide agonist. The peptide agonist retains an α-helical conformation as it sits deep within the receptor-binding pocket. The arrangement of the transmembrane helices reveals hallmarks of an active conformation similar to that observed in class A receptors. Guided by this structural information, we design peptide agonists with potent in vivo activity in a mouse model of diabetes.

Corrigendum: Crystal structure of the GLP-1 receptor bound to a peptide agonist.

This corrects the article DOI: 10.1038/nature22800.

Exploring the association between early adaptive schemas and self-reported eating disorder symptomatology.

OBJECTIVE: The current study aimed to examine the relationship between early adaptive schemas and eating disorder symptomatology in adults. METHOD: A cross-sectional, correlational design was used to collect data from 352 females and 36 males aged between 18 and 49 years (M = 25.70, SD = 7.04). Participants completed an online questionnaire, which included The Young Positive Schema Questionnaire (YPSQ), Eating Disorder Examination-Questionnaire (EDE-Q) and demographic measures. RESULTS: Four separate hierarchical multiple regression analyses showed that high levels of Healthy Boundaries and low levels of Optimism significantly predicted lower Restraint, Eating Concern, Shape Concern and Weight Concern scores. Additionally, higher scores in Emotional Openness and Social Belonging significantly predicted lower Eating Concern, while higher scores in Self-Care significantly predicted lower levels of Shape Concern. CONCLUSION: The findings highlight the protective function that certain early adaptive schemas may play in mitigating eating disorder symptomatology. Moreover, the findings allude to potential modifiable therapy targets in the treatment of eating disorders. Further research is needed to investigate any differences in early adaptive schemas between eating disorder diagnoses.

The emotionally exhausted treating the mentally unwell? A systematic review of burnout and stress interventions for psychologists.

Healthcare providers are at high risk of occupational burnout, which has negative implications on the individual, their profession, the organisation and their patients. Psychologists are particularly susceptible to the repercussions of burnout due to the emotionally draining nature and content of their work. However, research has failed to outline and evaluate effective interventions for burnout within the profession. This study aimed to investigate the treatment effectiveness of burnout through a systematic literature review. Systematic searches of four databases using Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were conducted. A total of 4832 articles were identified, and 15 were included in the final analysis. The search was limited to scholarly and peer-reviewed journals published in the English language, which measured and utilised a form of intervention for the treatment of burnout or stress and included participants within the psychology profession. Interventions identified included mindfulness, training courses, self-care and other therapy-based forms of interventions. Approximately 60% of study participants reported moderate to high levels of stress. Interventions were largely variable in modality, frequency and duration of sessions and follow-up period. Of the 15 studies included within the review, only four measured burnout as an outcome variable, while the others measured stress. Findings of this systematic review indicate that mindfulness-based interventions may be a starting point for reducing stress; however, the most effective intervention for psychologists who have reached burnout is largely unclear. It is recommended that future studies focus on the identification and measurement of burnout, are more rigorously designed and reported and consider peer-based online support approaches.

Factor structure of the Young Positive Schema Questionnaire in an eating disorder sample.

PURPOSE: The Young Positive Schema Questionnaire (YPSQ) measures early adaptive schemas (EAS) which could be used to develop positive psychology and schema-based interventions to benefit the treatment of eating disorders (EDs). METHODS: The present study investigated the factor structure of the YPSQ in a sample of 826 participants (18-73 years; n = 753 women) with ED symptomatology (e.g., restricting, binging, and purging). The sample was randomly split into two groups for exploratory and confirmatory factor analyses. Full sample analysis using Pearson correlations was conducted to explore convergent validity of the new YSPQ factor structure with ED symptomatology, emotional regulation, and cognitive flexibility. RESULTS: A nine-factor model was found, demonstrating good fit indices and internal consistency (α = 0.77-0.92). The YPSQ showed an inverse relationship to ED symptomatology and emotional suppression, and a positive relationship with cognitive flexibility and emotion reappraisal. CONCLUSION: Further research is needed to explore the clinical benefits of the YPSQ to identify EAS deficits in individuals with EDs to improve treatment outcomes. LEVEL OF EVIDENCE: Level V, descriptive study.

Intracellular allosteric antagonism of the CCR9 receptor.

Chemokines and their G-protein-coupled receptors play a diverse role in immune defence by controlling the migration, activation and survival of immune cells. They are also involved in viral entry, tumour growth and metastasis and hence are important drug targets in a wide range of diseases. Despite very significant efforts by the pharmaceutical industry to develop drugs, with over 50 small-molecule drugs directed at the family entering clinical development, only two compounds have reached the market: maraviroc (CCR5) for HIV infection and plerixafor (CXCR4) for stem-cell mobilization. The high failure rate may in part be due to limited understanding of the mechanism of action of chemokine antagonists and an inability to optimize compounds in the absence of structural information. CC chemokine receptor type 9 (CCR9) activation by CCL25 plays a key role in leukocyte recruitment to the gut and represents a therapeutic target in inflammatory bowel disease. The selective CCR9 antagonist vercirnon progressed to phase 3 clinical trials in Crohn's disease but efficacy was limited, with the need for very high doses to block receptor activation. Here we report the crystal structure of the CCR9 receptor in complex with vercirnon at 2.8 Å resolution. Remarkably, vercirnon binds to the intracellular side of the receptor, exerting allosteric antagonism and preventing G-protein coupling. This binding site explains the need for relatively lipophilic ligands and describes another example of an allosteric site on G-protein-coupled receptors that can be targeted for drug design, not only at CCR9, but potentially extending to other chemokine receptors.

Early maladaptive schemas in eating disorders: A systematic review.

OBJECTIVE: Research and theory suggest the aetiological nature and symptomatic profile of eating disorders (EDs) can be explained by multiple factors, including the development of early maladaptive schemas (EMS). Yet, there is lack of consensus regarding the evidence supporting the relationship between EMS and EDs. Therefore, this systematic review aimed to examine existing literature concerning the relationship between different ED diagnoses and EMS to provide a synthesis and evaluation of relevant research. METHOD: A comprehensive literature search of four electronic databases was conducted and studies were included that examined the association between EMS and EDs. Studies were required to use a variant of Young Schema Questionnaire and establish ED diagnosis or symptomology using self-report questionnaires or clinical interview. RESULTS: A total of 29 studies were included in the review. Compared to healthy controls and varying clinical populations, individuals with EDs generally reported significantly higher scores across all EMS except for Entitlement. Furthermore, Unrelenting Standards consistently appeared as a significant EMS across all ED diagnoses whilst Insufficient Self-Control was significantly lower in ED diagnoses with restrictive behaviour compared to diagnoses with binge eating or purging behaviour. DISCUSSION: Research supports significant associations between EMS and EDs, which may contribute to our understanding of ED aetiology, including different diagnostic categories. This review underscores the need for studies to explore more gender and age diverse samples and highlights important implications for practitioners.

Model Unity and the Unity of Consciousness: Developments in Expected Float Entropy Minimisation.

The unity of consciousness, or, more precisely, phenomenal unity, is an important property of consciousness and an important area of research in mathematical consciousness science and the scientific study of consciousness. Due to the numerous aspects and complexity of consciousness, the property tends to engender loose or inadequate characterizations. In this article, we introduce the concept and mathematical formulation of model unity. A system has model unity if a single relational model, stretched across the whole system, is optimal. Alternatively, model unity may only be present for subsystems, although there may still be unity at some higher level. As a development in the theory of expected float entropy minimisation, such relational models provide an interpretation of system states and the theory may help to provide insights into questions such as why experience of the visual field is unified and why different people do not have a unified consciousness, for example. This article constitutes a relatively small initial study of model unity. Four investigations were undertaken and are given as examples. A postulate is also given, distilling the foundations of EFE minimisation into a clear statement allowing others to consider whether or not the postulate identifies a self-evident fundamental property of consciousness.

Blur resolved OCT: full-range interferometric synthetic aperture microscopy through dispersion encoding.

We present a computational method for full-range interferometric synthetic aperture microscopy (ISAM) under dispersion encoding. With this, one can effectively double the depth range of optical coherence tomography (OCT), whilst dramatically enhancing the spatial resolution away from the focal plane. To this end, we propose a model-based iterative reconstruction (MBIR) method, where ISAM is directly considered in an optimization approach, and we make the discovery that sparsity promoting regularization effectively recovers the full-range signal. Within this work, we adopt an optimal nonuniform discrete fast Fourier transform (NUFFT) implementation of ISAM, which is both fast and numerically stable throughout iterations. We validate our method with several complex samples, scanned with a commercial SD-OCT system with no hardware modification. With this, we both demonstrate full-range ISAM imaging and significantly outperform combinations of existing methods.

Accurate Prediction of GPCR Ligand Binding Affinity with Free Energy Perturbation.

The computational prediction of relative binding free energies is a crucial goal for drug discovery, and G protein-coupled receptors (GPCRs) are arguably the most important drug target class. However, they present increased complexity to model compared to soluble globular proteins. Despite breakthroughs, experimental X-ray crystal and cryo-EM structures are challenging to attain, meaning computational models of the receptor and ligand binding mode are sometimes necessary. This leads to uncertainty in understanding ligand-protein binding induced changes such as, water positioning and displacement, side chain positioning, hydrogen bond networks, and the overall structure of the hydration shell around the ligand and protein. In other words, the very elements that define structure activity relationships (SARs) and are crucial for accurate binding free energy calculations are typically more uncertain for GPCRs. In this work we use free energy perturbation (FEP) to predict the relative binding free energies for ligands of two different GPCRs. We pinpoint the key aspects for success such as the important role of key water molecules, amino acid ionization states, and the benefit of equilibration with specific ligands. Initial calculations following typical FEP setup and execution protocols delivered no correlation with experiment, but we show how results are improved in a logical and systematic way. This approach gave, in the best cases, a coefficient of determination (R2) compared with experiment in the range of 0.6-0.9 and mean unsigned errors compared to experiment of 0.6-0.7 kcal/mol. We anticipate that our findings will be applicable to other difficult-to-model protein ligand data sets and be of wide interest for the community to continue improving FE binding energy predictions.