Development of a Novel Assay for Direct Assessment of Selective Amylin Receptor Activation Reveals Novel Differences in Behavior of Selective and Nonselective Peptide Agonists.

Dual amylin and calcitonin receptor agonists (DACRAs) show promise as efficacious therapeutics for treatment of metabolic disease, including obesity. However, differences in efficacy in vivo have been observed for individual DACRAs, indicating that detailed understanding of the pharmacology of these agents across target receptors is required for rational drug development. To date, such understanding has been hampered by lack of direct, subtype-selective, functional assays for the amylin receptors (AMYRs). Here, we describe the generation of receptor-specific assays for recruitment of Venus-tagged Gs protein through fusion of luciferase to either the human calcitonin receptor (CTR), human receptor activity-modifying protein (RAMP)-1, RAMP1 (AMY1R), human RAMP2 (AMY2R), or human RAMP3 (AMY3R). These assays revealed a complex pattern of receptor activation by calcitonin, amylin, or DACRA peptides that was distinct at each receptor subtype. Of particular note, although both of the CT-based DACRAs, sCT and AM1784, displayed relatively similar behaviors at CTR and AMY1R, they generated distinct responses at AMY2R and AMY3R. These data aid the rationalization of in vivo differences in response to DACRA peptides in rodent models of obesity. Direct assessment of the pharmacology of novel DACRAs at AMYR subtypes is likely to be important for development of optimized therapeutics for treatment of metabolic diseases. SIGNIFICANCE STATEMENT: Amylin receptors (AMYRs) are important obesity targets. Here we describe a novel assay that allows selective functional assessment of individual amylin receptor subtypes that provides unique insight into the pharmacology of potential therapeutic ligands. Direct assessment of the pharmacology of novel agonists at AMYR subtypes is likely to be important for development of optimized therapeutics for treatment of metabolic diseases.

Lipid-Dependent Activation of the Orphan G Protein-Coupled Receptor, GPR3.

The class A orphan G protein-coupled receptor (GPCR), GPR3, has been implicated in a variety of conditions, including Alzheimer's and premature ovarian failure. GPR3 constitutively couples with Gαs, resulting in the production of cAMP in cells. While tool compounds and several putative endogenous ligands have emerged for the receptor, its endogenous ligand, if it exists, remains a mystery. As novel potential drug targets, the structures of orphan GPCRs have been of increasing interest, revealing distinct modes of activation, including autoactivation, presence of constitutively activating mutations, or via cryptic ligands. Here, we present a cryo-electron microscopy (cryo-EM) structure of the orphan GPCR, GPR3 in complex with DNGαs and Gß1γ2. The structure revealed clear density for a lipid-like ligand that bound within an extended hydrophobic groove, suggesting that the observed "constitutive activity" was likely due to activation via a lipid that may be ubiquitously present. Analysis of conformational variance within the cryo-EM data set revealed twisting motions of the GPR3 transmembrane helices that appeared coordinated with changes in the lipid-like density. We propose a mechanism for the binding of a lipid to its putative orthosteric binding pocket linked to the GPR3 dynamics.

Digital Biomarkers for Depression Screening With Wearable Devices: Cross-sectional Study With Machine Learning Modeling.

BACKGROUND: Depression is a prevalent mental disorder that is undiagnosed and untreated in half of all cases. Wearable activity trackers collect fine-grained sensor data characterizing the behavior and physiology of users (ie, digital biomarkers), which could be used for timely, unobtrusive, and scalable depression screening. OBJECTIVE: The aim of this study was to examine the predictive ability of digital biomarkers, based on sensor data from consumer-grade wearables, to detect risk of depression in a working population. METHODS: This was a cross-sectional study of 290 healthy working adults. Participants wore Fitbit Charge 2 devices for 14 consecutive days and completed a health survey, including screening for depressive symptoms using the 9-item Patient Health Questionnaire (PHQ-9), at baseline and 2 weeks later. We extracted a range of known and novel digital biomarkers characterizing physical activity, sleep patterns, and circadian rhythms from wearables using steps, heart rate, energy expenditure, and sleep data. Associations between severity of depressive symptoms and digital biomarkers were examined with Spearman correlation and multiple regression analyses adjusted for potential confounders, including sociodemographic characteristics, alcohol consumption, smoking, self-rated health, subjective sleep characteristics, and loneliness. Supervised machine learning with statistically selected digital biomarkers was used to predict risk of depression (ie, symptom severity and screening status). We used varying cutoff scores from an acceptable PHQ-9 score range to define the depression group and different subsamples for classification, while the set of statistically selected digital biomarkers remained the same. For the performance evaluation, we used k-fold cross-validation and obtained accuracy measures from the holdout folds. RESULTS: A total of 267 participants were included in the analysis. The mean age of the participants was 33 (SD 8.6, range 21-64) years. Out of 267 participants, there was a mild female bias displayed (n=170, 63.7%). The majority of the participants were Chinese (n=211, 79.0%), single (n=163, 61.0%), and had a university degree (n=238, 89.1%). We found that a greater severity of depressive symptoms was robustly associated with greater variation of nighttime heart rate between 2 AM and 4 AM and between 4 AM and 6 AM; it was also associated with lower regularity of weekday circadian rhythms based on steps and estimated with nonparametric measures of interdaily stability and autocorrelation as well as fewer steps-based daily peaks. Despite several reliable associations, our evidence showed limited ability of digital biomarkers to detect depression in the whole sample of working adults. However, in balanced and contrasted subsamples comprised of depressed and healthy participants with no risk of depression (ie, no or minimal depressive symptoms), the model achieved an accuracy of 80%, a sensitivity of 82%, and a specificity of 78% in detecting subjects at high risk of depression. CONCLUSIONS: Digital biomarkers that have been discovered and are based on behavioral and physiological data from consumer wearables could detect increased risk of depression and have the potential to assist in depression screening, yet current evidence shows limited predictive ability. Machine learning models combining these digital biomarkers could discriminate between individuals with a high risk of depression and individuals with no risk.

The importance of air quality for underground spaces: An international survey of public attitudes.

Space is a resource that is constantly being depleted, especially in mega-cities. Underground workspaces (UGS) are increasingly being included in urban plans and have emerged as an essential component of vertical cities. While progress had been made on the engineering aspects associated with the development of high-quality UGS, public attitudes toward UGS as work environments (ie, the public's design concerns with UGS) are relatively unknown. Here, we present the first large-scale study examining preferences and attitudes toward UGS, surveying close to 2000 participants from four cities in three continents (Singapore, Shanghai, London, and Montreal). Contrary to previous beliefs, air quality (and not lack of windows) is the major concern of prospective occupants. Windows, temperature, and lighting emerged as additional important building performance aspects for UGS. Early adopters (ie, individuals more willing to accept UGS and thus more likely to be the first occupants) across all cities prioritized air quality. Present results suggest that (perceived) air quality is a key building performance aspect for UGS that needs to be communicated to prospective occupants as this will improve their attitudes and views toward UGS. This study highlights the importance of indoor air quality for the public.

A Comparative Study of International and Asian Criteria for Overweight or Obesity at Workplaces in Singapore.

To compare the prevalence of and risk factors associated with overweight or obesity between the international (body mass index [BMI] ≥25 kg/m2) and Asian (BMI ≥23 kg/m2) criteria in a working population in Singapore. This was a cross-sectional analysis of a cohort study of 464 employees (aged ≥21 years) conducted at 4 workplaces in Singapore. The prevalence of overweight or obesity was 47.4% and 67.0% with the international and Asian criteria, respectively. With both the criteria, higher age, male sex, Malay ethnicity (vs Chinese), lower white rice intake, and consumption of sugar-sweetened beverages were positively associated with overweight or obesity. Participants with poorer mental health and higher levels of thermal comfort in the workplace were positively associated with overweight or obesity only with the Asian criteria. The use of international criteria alone in this population could have overlooked these risk factors that are highly relevant to the Singapore context.

Fulminant necrotizing fasciitis to the hand in a patient on high-dose steroids: A case report of successful limb salvage.

Glucocorticoids are commonly used in the management of patients with brain Tumour for reducing peritumoral and vasogenic edema. However, they may lead to development of limb and life-threatening conditions such as necrotizing fasciitis (NF). NF is a rare but potentially lethal condition. Early detection and aggressive treatment may lead to decreased mortality and limb salvage. The diagnosis is predominately clinical but may be supported by laboratory and radiological investigations. Chronic steroid use not only predisposes to the development of NF but also may mask early features delaying presentation and diagnosis. Clinicians should have a high index of suspicion especially in patients on chronic steroid therapy as this may aid in early detection and treatment. We present a case report of a successful limb salvage that exemplifies these points.

Factors associated with health-related quality of life in a working population in Singapore.

OBJECTIVES: This study aimed to evaluate the determinants of health-related quality of life (HRQoL) among workers in Singapore. METHODS: We analysed data from a cross-sectional study of 464 participants from 4 companies in Singapore. Physical and mental components of HRQoL were assessed using the Short-Form 36 version 2.0 survey. A generalized linear model was used to determine factors associated with the physical component summary (PCS) and mental component summary (MCS) scores of HRQoL. RESULTS: The overall mean PCS and MCS scores were mean±standard deviation 51.6±6.7 and 50.2±7.7, respectively. The scores for subscales ranged from 62.7±14.7 for vitality to 83.5±20.0 for role limitation due to emotional problems. Ethnicity, overweight/obesity, and years working at the company were significantly associated with physical HRQoL, and age and stress at work were significantly associated with mental HRQoL. Moreover, sleep quality was significantly associated with both physical and mental HRQoL. CONCLUSIONS: These findings could help workplaces in planning strategies and initiatives for employees to maintain a worklife balance that encompasses their physical, emotional, and social well-being.

Employee experiences in underground workplaces: a qualitative investigation.

Underground workplaces (UWS) are increasingly being recognised as a sustainable solution to concerns regarding lack of space facing megacities. UWS can multiply available space by reducing urban sprawl thereby improving quality of life in cities. However, developing workplaces that respond to the needs and preferences of occupants will be a crucial factor in determining the success of this concept. We examine the experiences of existing full-time employees of a large underground facility in North America and analyse how these are related to company policies and other organisational factors. From in-depth interviews of 73 participants, three predominant themes emerged from the analyses: environmental effects (e.g. lack of sunlight), design (e.g. the unique working environment), and organisational factors and social dynamics (e.g. policies regarding breaks). We discuss these themes in relation with interventions that may improve employee comfort and retention and suggest that many factors are within organisational control. Practitioner Summary: Underground workplaces are a sustainable solution to lack of urban space. However, developing effective workplaces is crucial to their success. We examine the experiences of existing employees of an underground facility in North America. We suggest that most negative attitudes towards underground spaces can be mitigated through simple organisational interventions. Abbreviations: UWS: underground workplaces; IRB: institutional review board.

Associations of perceived indoor environmental quality with stress in the workplace.

Indoor environmental quality (IEQ) is a general indicator of the quality of conditions inside a building. We investigated associations of perceived IEQ including air quality, thermal comfort, noise, and light quality with stress at work and the extent to which workplace location modifies these associations. We recruited 464 full-time workers from four companies in Singapore. Data on socio-demographic characteristics, lifestyle/health-related factors, and workplace factors were collected through self-administered questionnaires. Perceived IEQ satisfaction scores of all four factors were collected using the validated OFFICAIR questionnaire. We fitted a logistic regression model to assess associations between each perceived IEQ score and stress at work, adjusting for potential confounders. The odds ratio for stress at work associated with a 1-unit increase in perceived air quality score was 0.88 (0.82-0.94), 0.89 (0.82-0.97) for thermal comfort, 0.93 (0.87-0.98) for noise, and 0.88 (0.82-0.94) for light quality. Significant associations were found in office and control rooms for all four perceived IEQ, except for thermal comfort in office rooms. Higher satisfaction levels of perceived air quality, thermal comfort, noise, and lighting, were significantly associated with a reduction in stress at work. Our findings could potentially provide a useful tool for environmental health impact assessment for buildings.

The multicultural mind as an epistemological test and extension for the thinking through other minds approach.

The multicultural experience (i.e., multicultural individuals and cross-cultural experiences) offers the intriguing possibility for (i) an empirical examination of how free-energy principles explain dynamic cultural behaviors and pragmatic cultural phenomena and (ii) a challenging but decisive test of thinking through other minds (TTOM) predictions. We highlight that TTOM needs to treat individuals as active cultural agents instead of passive learners.

Association between shift work and poor sleep quality in an Asian multi-ethnic working population: A cross-sectional study.

BACKGROUND: We aimed to examine the association between shift work and sleep quality in a diverse occupational type. METHODS: This was a cross-sectional study of self-reported sleep quality in 424 workers aged ≥21 using the Pittsburgh Sleep Quality Index (PSQI). We divided workers into two categories based on their PSQI score: (a) ≤5 (good sleep quality) and (b) >5 (poor sleep quality). We used multiple logistic regressions to assess the association between shift work and sleep quality adjusted for potential confounders. RESULTS: The mean age was 39.2 (SD = 11.3) years, with shift workers being older than their counterparts. Most workers were of Chinese ethnicity (63.9%). Males were significantly more likely to undertake shift work than females (89% v 11%, p-value<0.001), but it should be noted that the majority of workers was male (78.8%) in this sample of workers. Shift workers had a 198% increased odds of poor sleep quality compared to non-shift workers (OR = 2.98; 95% CI:1.53-5.81). CONCLUSION: Shift work was significantly and independently associated with increased odds of poor sleep quality in this sample of workers. The present findings may inform employment guidelines and help develop workplace health promotion interventions aimed at improving sleep quality among workers and ultimately lead to a healthier workforce.

Activity Tracker-Based Metrics as Digital Markers of Cardiometabolic Health in Working Adults: Cross-Sectional Study.

BACKGROUND: Greater adoption of wearable devices with multiple sensors may enhance personalized health monitoring, facilitate early detection of some diseases, and further scale up population health screening. However, few studies have explored the utility of data from wearable fitness trackers in cardiovascular and metabolic disease risk prediction. OBJECTIVE: This study aimed to investigate the associations between a range of activity metrics derived from a wearable consumer-grade fitness tracker and major modifiable biomarkers of cardiometabolic disease in a working-age population. METHODS: This was a cross-sectional study of 83 working adults. Participants wore Fitbit Charge 2 for 21 consecutive days and went through a health assessment, including fasting blood tests. The following clinical biomarkers were collected: BMI, waist circumference, waist-to-hip ratio, blood pressure, triglycerides (TGs), high-density lipoprotein (HDL) and low-density lipoprotein cholesterol, and blood glucose. We used a range of wearable-derived metrics based on steps, heart rate (HR), and energy expenditure, including measures of stability of circadian activity rhythms, sedentary time, and time spent at various intensities of physical activity. Spearman rank correlation was used for preliminary analysis. Multiple linear regression adjusted for potential confounders was used to determine the extent to which each metric of activity was associated with continuous clinical biomarkers. In addition, pairwise multiple regression was used to investigate the significance and mutual dependence of activity metrics when two or more of them had significant association with the same outcome from the previous step of the analysis. RESULTS: The participants were predominantly middle aged (mean age 44.3 years, SD 12), Chinese (62/83, 75%), and male (64/83, 77%). Blood biomarkers of cardiometabolic disease (HDL cholesterol and TGs) were significantly associated with steps-based activity metrics independent of age, gender, ethnicity, education, and shift work, whereas body composition biomarkers (BMI, waist circumference, and waist-to-hip ratio) were significantly associated with energy expenditure-based and HR-based metrics when adjusted for the same confounders. Steps-based interdaily stability of circadian activity rhythm was strongly associated with HDL (beta=5.4 per 10% change; 95% CI 1.8 to 9.0; P=.005) and TG (beta=-27.7 per 10% change; 95% CI -48.4 to -7.0; P=.01). Average daily steps were negatively associated with TG (beta=-6.8 per 1000 steps; 95% CI -13.0 to -0.6; P=.04). The difference between average HR and resting HR was significantly associated with BMI (beta=-.5; 95% CI -1.0 to -0.1; P=.01) and waist circumference (beta=-1.3; 95% CI -2.4 to -0.2; P=.03). CONCLUSIONS: Wearable consumer-grade fitness trackers can provide acceptably accurate and meaningful information, which might be used in the risk prediction of cardiometabolic disease. Our results showed the beneficial effects of stable daily patterns of locomotor activity for cardiometabolic health. Study findings should be further replicated with larger population studies.

Toward a Structural Understanding of Class B GPCR Peptide Binding and Activation.

Class B G protein-coupled receptors (GPCRs) are important therapeutic targets for major diseases. Here, we present structures of peptide and Gs-bound pituitary adenylate cyclase-activating peptide, PAC1 receptor, and corticotropin-releasing factor (CRF), (CRF1) receptor. Together with recently solved structures, these provide coverage of the major class B GPCR subfamilies. Diverse orientations of the extracellular domain to the receptor core in different receptors are at least partially dependent on evolutionary conservation in the structure and nature of peptide interactions. Differences in peptide interactions to the receptor core also influence the interlinked TM2-TM1-TM6/ECL3/TM7 domain, and this is likely important in their diverse signaling. However, common conformational reorganization of ECL2, linked to reorganization of ICL2, modulates G protein contacts. Comparison between receptors reveals ICL2 as a key domain forming dynamic G protein interactions in a receptor- and ligand-specific manner. This work advances our understanding of class B GPCR activation and Gs coupling.

Anti-Müllerian hormone (AMH) in the Diagnosis of Menstrual Disturbance Due to Polycystic Ovarian Syndrome.

Introduction: Polycystic ovarian syndrome (PCOS) is a leading cause of female subfertility worldwide, however due to the heterogeneity of the disorder, the criteria for diagnosis remains subject to conjecture. In the present study, we evaluate the utility of serum Anti-Müllerian hormone (AMH) in the diagnosis of menstrual disturbance due to PCOS. Method: Menstrual cycle length, serum AMH, gonadotropin and sex-hormone levels, total antral follicle count (AFC), body mass index (BMI) and ovarian morphology on ultrasound were analyzed in a cohort of 187 non-obese women, aged 18-35 years, screened for participation in a clinical trial of fertility treatment between 2013 and 2016 at a tertiary reproductive endocrine center. Results: Serum AMH was higher in women with menstrual disturbance when compared to those with regular cycles (65.6 vs. 34.8 pmol/L; P < 0.0001). The odds of menstrual disturbance was increased 28.5-fold (95% CI 3.6-227.3) in women with serum AMH >60 pmol/L, in comparison to those with an AMH < 15 pmol/L. AMH better discriminated women with menstrual disturbance (area under ROC 0.77) from those with regular menstrual cycles than AFC (area under ROC 0.67), however the combination of the two markers increased discrimination than either measure alone (0.83; 95% CI 0.77-0.89). Serum AMH was higher in women with all three cardinal features of PCOS (menstrual disturbance, hyperandrogenism, polycystic ovarian morphology) when compared to women with none of these features (65.6 vs. 14.6 pmol/L; P < 0.0001). The odds of menstrual disturbance were increased by 10.7-fold (95% CI 2.4-47.1) in women with bilateral polycystic morphology ovaries than those with normal ovarian morphology. BMI was a stronger predictor of free androgen index (FAI) than either AMH or AFC. Conclusion: Serum AMH could serve as a useful biomarker to indicate the risk of menstrual disturbance due to PCOS. Women with higher AMH levels had increased rates of menstrual disturbance and an increased number of features of PCOS.

Cultural Attachment: From Behavior to Computational Neuroscience.

Cultural attachment (CA) refers to processes that allow culture and its symbols to provide psychological security when facing threat. Epistemologically, whereas we currently have an adequate predictivist model of CA, it is necessary to prepare for a mechanistic approach that will not only predict, but also explain CA phenomena. Toward that direction, we here first examine the concepts and mechanisms that are the building blocks of both the prototypical maternal attachment as well as CA. Based on existing robust neuroscience models we associate these concepts and mechanisms with bona fide neurobiological functions to advance an integrative neurobiological model of CA. We further discuss the unresolved relationship of CA to other similar socio-cognitive concepts such as familiarity. Overall aim of the paper is to highlight the importance of integrating CA theory to computational approaches to culture and evolution (such as predictive processing computations explaining niche construction), as this will allow a dynamic interpretation of cultural processes.

Assessing the suitability of virtual reality for psychological testing.

Virtual reality (VR) is rapidly becoming an inexpensive, mainstream technology. VR technology is superambulatory as it allows participants to be examined under standardized environments and tests anywhere. In addition, it can test participants in different virtual spaces, including environments that are unsafe, inaccessible, costly or difficult to set up, or even nonexistent. We summarize the benefits and potential problems of VR technology, but we also move beyond theoretical approaches and present a customizable, open-source VR system (PSY-VR) that allows scalable psychological testing in modifiable VR environments. This system allows users to modify the environment using a simple graphical interface, without programming expertise. Moreover, as a proof-of-concept, we compare responses in a typical Flanker task between a real laboratory and a painstakingly matched virtual laboratory. Results indicate that the VR responses are comparable to real life testing, demonstrating the utility of VR for psychological assessment studies. The predicted rapid advancement of VR immersive technologies, as well the ease of their integration with physiological metrics ensures that VR-based assessment will be the modus operandi of psychological assessment in the future. This will allow controllable, low-cost assessment on a global scale. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Melatonin and health: an umbrella review of health outcomes and biological mechanisms of action.

BACKGROUND: Our aims were to evaluate critically the evidence from systematic reviews as well as narrative reviews of the effects of melatonin (MLT) on health and to identify the potential mechanisms of action involved. METHODS: An umbrella review of the evidence across systematic reviews and narrative reviews of endogenous and exogenous (supplementation) MLT was undertaken. The Oxman checklist for assessing the methodological quality of the included systematic reviews was utilised. The following databases were searched: MEDLINE, EMBASE, Web of Science, CENTRAL, PsycINFO and CINAHL. In addition, reference lists were screened. We included reviews of the effects of MLT on any type of health-related outcome measure. RESULTS: Altogether, 195 reviews met the inclusion criteria. Most were of low methodological quality (mean -4.5, standard deviation 6.7). Of those, 164 did not pool the data and were synthesised narratively (qualitatively) whereas the remaining 31 used meta-analytic techniques and were synthesised quantitatively. Seven meta-analyses were significant with P values less than 0.001 under the random-effects model. These pertained to sleep latency, pre-operative anxiety, prevention of agitation and risk of breast cancer. CONCLUSIONS: There is an abundance of reviews evaluating the effects of exogenous and endogenous MLT on health. In general, MLT has been shown to be associated with a wide variety of health outcomes in clinically and methodologically heterogeneous populations. Many reviews stressed the need for more high-quality randomised clinical trials to reduce the existing uncertainties.

A Psychosocial Approach to Understanding Underground Spaces.

With a growing need for usable land in urban areas, subterranean development has been gaining attention. While construction of large underground complexes is not a new concept, our understanding of various socio-cultural aspects of staying underground is still at a premature stage. With projected emergence of underground built environments, future populations may spend much more of their working, transit, and recreational time in underground spaces. Therefore, it is essential to understand the challenges and advantages that such environments have to improve the future welfare of users of underground spaces. The current paper discusses various psycho-social aspects of underground spaces, the impact they can have on the culture shared among the occupants, and possible solutions to overcome some of these challenges.

Phase-plate cryo-EM structure of a class B GPCR-G-protein complex.

Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, such as osteoporosis, diabetes and obesity. Here we report the structure of a full-length class B receptor, the calcitonin receptor, in complex with peptide ligand and heterotrimeric Gαsßγ protein determined by Volta phase-plate single-particle cryo-electron microscopy. The peptide agonist engages the receptor by binding to an extended hydrophobic pocket facilitated by the large outward movement of the extracellular ends of transmembrane helices 6 and 7. This conformation is accompanied by a 60° kink in helix 6 and a large outward movement of the intracellular end of this helix, opening the bundle to accommodate interactions with the α5-helix of Gαs. Also observed is an extended intracellular helix 8 that contributes to both receptor stability and functional G-protein coupling via an interaction with the Gß subunit. This structure provides a new framework for understanding G-protein-coupled receptor function.