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Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.

Mapping and dating former glacial margins is a key tool for assessing the sensitivity of glaciers to changing climate conditions, both past and future. However in many regions, such as along the northeastern margins of the North Atlantic, direct chronologic control on past glacier extent can be sparse. In particular, the former extent and elevation of the Irish Ice Sheet (IIS) during the Last Glacial Maximum (LGM; 26-19 ka) and subsequent termination remain a topic of debate - due in part to the coarse resolution of existing (direct) age control on glacial margins. This includes the margins of former valley and cirque glaciers that nucleated in the Irish highlands after local retreat of the IIS. In eastern Ireland, the Wicklow Mountains host numerous valley and cirque moraines that are largely undated, evidence of past glacial fluctuations following the LGM. Here we report new geomorphic mapping and cosmogenic beryllium-10 surface-exposure ages of moraines in the Glen of Imaal in the southwestern Wicklow Mountains. Our preliminary beryllium-10 ages provide new chronologic constraint on the extent of glaciers in the Glen of Imaal following the LGM. We also compare our preliminary glacial chronology with records of wider North Atlantic climate to investigate the response of ice in the Glen of Imaal to changing climate conditions. These data provide new insight on Ireland’s glacial past, and yield vital information on climate and glaciation in the wider North Atlantic region.

Emotion recognition is a complex nonlinear process, and there is debate regarding whether it is an automatic process, or whether it involves working memory (WM) or attentional resources. Evidence suggests that individuals with ADHD exhibit impairments in emotion recognition, though the driving forces behind these impairments are unclear. This project aimed to measure the role of attentional resources on emotion recognition in adults with ADHD by using a dual-task experiment involving a WM loading task and a dynamic face morphing paradigm. Participants were asked to identify the emotion expression shown in dynamic video morph sequences that changed rapidly from neutral to 80% intensity and back. This was performed in two conditions: alone and with a concurrent WM number recall task. Participant mood state and levels of anxiety and depressive symptoms were measured and controlled for using two self-report questionnaires (PANAS & Mini-MASQ). It was hypothesised that if emotion recognition requires attention, additional WM load would result in dual-task costs to emotion recognition performance in general, but especially for ADHD participants. No dual-task costs were found across groups in emotion recognition, though the results did reveal deficits in general WM performance for the ADHD group consistent with the wider literature. Taken altogether, the results emphasise the complexity of attentional/WM considerations and highlight the need for further research utilising similar dynamic paradigms.

We investigated whether the reward that has previously been associated with initiated joint attention (the experience of having one’s gaze followed by someone else; Pfeiffer et al., 2014, Schilbach et al., 2010) can influence gaze behaviour and, similarly to monetary rewards (Blaukopf & DiGirolamo, 2005; Manohar et al., 2017; Milstein & Dorris, 2007), elicit learning effects. To this end, we adapted Milstein and Dorris (2007) gaze contingent paradigm, so it required participants to look at an anthropomorphic avatar and then conduct a saccade towards the left or right peripheral target. If participants were fast enough, they could experience social reward in terms of the avatar looking at the same target as they did and thus engaging with them in joint attention. One side had higher reward probability than the other (80 % vs 20 %; on the other fast trials the avatar would simply keep staring ahead). We expected that if participants learned about the reward contingency and if they found the experience of having their gaze followed rewarding, their latency and success rate would improve for saccades to the high rewarded targets. Although our current study did not demonstrate that such social reward has a long lasting effect on gaze behaviour, we found that latencies became shorter over time and that latencies were longer on congruent trials (target location was identical to the previous trial) than on noncongruent trials (target location different than on the previous trial), which could reflect inhibition of return.

Objective: Hypothalamic melanocortin 4 receptors (MC4R) are a key regulator of energy homeostasis. Brain-penetrant MC4R agonists have failed, as concentrations required to suppress food intake also increase blood pressure. However, peripherally located MC4R may also mediate metabolic benefits of MC4R activation. Mc4r transcript is enriched in mouse enteroendocrine L cells and peripheral administration of the endogenous MC4R agonist, α-melanocyte stimulating hormone (α-MSH), triggers the release of the anorectic hormones Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in mice. This study aimed to determine whether pathways linking MC4R and L-cell secretion exist in humans. Design: GLP-1 and PYY levels were assessed in body mass index–matched individuals with or without loss-of-function MC4R mutations following an oral glucose tolerance test. Immunohistochemistry was performed on human intestinal sections to characterize the mucosal MC4R system. Static incubations with MC4R agonists were carried out on human intestinal epithelia, GLP-1 and PYY contents of secretion supernatants were assayed. Results: Fasting PYY levels and oral glucose-induced GLP-1 secretion were reduced in humans carrying a total loss-of-function MC4R mutation. MC4R was localized to L cells and regulates GLP-1 and PYY secretion from ex vivo human intestine. α-MSH immunoreactivity in the human intestinal epithelia was predominantly localized to L cells. Glucose-sensitive mucosal pro-opiomelanocortin cells provide a local source of α-MSH that is essential for glucose-induced GLP-1 secretion in small intestine. Conclusion: Our findings describe a previously unidentified signaling nexus in the human gastrointestinal tract involving α-MSH release and MC4R activation on L cells in an autocrine and paracrine fashion. Outcomes from this study have direct implications for targeting mucosal MC4R to treat human metabolic disorders. Refereed/Peer-reviewed

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited by the requirement for injection. Here we describe the first effective, orally bioavailable small molecule GLP-1R agonists. A sensitized high-throughput screen identified a series of small molecule GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nM potency. These small molecule agonists increased insulin levels in primates but not rodents, which is explained by a cryo-EM structure that revealed a binding pocket requiring primate-specific tryptophan 33. Importantly, oral administration of agonist PF-06882961 to healthy humans produced dose-dependent declines in serum glucose (NCT03309241). This opens the door to a new era of oral small molecule therapies that target the well-validated GLP-1R pathway for metabolic health.One Sentence SummaryPF-06882961 is an orally administered small molecule that activates the GLP-1 receptor to lower blood glucose in humans.

Visuo-spatial working memory (VSWM) helps track the identity and location of people during social interactions. Previous work showed better VSWM when all faces at encoding displayed a happy compared to an angry expression, reflecting a prosocial preference for monitoring who was where. However, social environments are not typically uniform, and certain expressions may more strongly compete for and bias face monitoring according to valence and/or arousal properties. Here we used heterogeneous encoding displays in which two faces shared one emotion and two shared another, and asked participants to relocate a central neutral probe face after a blank delay. When considering the emotion of the probed face independently of the co-occurring emotion at encoding, an overall happy benefit was replicated. However, accuracy was modulated by the non-probed emotion, with a relocation benefit for angry over sad, happy over fearful, and sad over happy faces. These effects did not depend on encoding fixation time, stimulus arousal, perceptual similarity, or response bias. Thus, emotional competition for faces in VSWM is complex and appears to rely on more than simple arousal- or valence- biased mechanisms. We propose a ‘social value’ account to better explain when and why certain emotions may be prioritised in VSWM.

This paper discusses solutions to cyberbullying posed by post-secondary students from four Canadian universities. The qualitative data used in this analysis were drawn from one open-ended question on an online student survey completed by 1458 undergraduate students, as well as 10 focus group transcripts involving a total of 36 students. Seven key themes emerged: awareness and education, policy, protecting one&rsquo, s privacy, technology-based solutions, empowering better choices and responses, university culture, and disciplinary measures. The findings show that post-secondary institutions need to make preventing and curtailing cyberbullying more of a priority within their campus communities, including engaging in responsive consultation with key stakeholder groups, such as students, to develop meaningful solutions.

This article explores how 13 Australian universities are assisting their researchers to manage the growing expectation to make research data more accessible. It identifies which university groups a...

Background/objectives: Evidence from animal studies highlights an important role for serotonin (5-HT), derived from gut enterochromaffin (EC) cells, in regulating hepatic glucose production, lipolysis and thermogenesis, and promoting obesity and dysglycemia. Evidence in humans is limited, although elevated plasma 5-HT concentrations are linked to obesity. Subjects/methods: We assessed (i) plasma 5-HT concentrations before and during intraduodenal glucose infusion (4 kcal/min for 30 min) in non-diabetic obese (BMI 44 ± 4 kg/m2, N = 14) and control (BMI 24 ± 1 kg/m2, N = 10) subjects, (ii) functional activation of duodenal EC cells (immunodetection of phospho-extracellular related-kinase, pERK) in response to glucose, and in separate subjects, (iii) expression of tryptophan hydroxylase-1 (TPH1) in duodenum and colon (N = 39), and (iv) 5-HT content in primary EC cells from these regions (N = 85). Results: Plasma 5-HT was twofold higher in obese than control responders prior to (P = 0.025), and during (iAUC, P = 0.009), intraduodenal glucose infusion, and related positively to BMI (R2 = 0.334, P = 0.003) and HbA1c (R2 = 0.508, P = 0.009). The density of EC cells in the duodenum was twofold higher at baseline in obese subjects than controls (P = 0.023), with twofold more EC cells activated by glucose infusion in the obese (EC cells co-expressing 5-HT and pERK, P = 0.001), while the 5-HT content of EC cells in duodenum and colon was similar; TPH1 expression was 1.4-fold higher in the duodenum of obese subjects (P = 0.044), and related positively to BMI (R2 = 0.310, P = 0.031). Conclusions: Human obesity is characterized by an increased capacity to produce and release 5-HT from the proximal small intestine, which is strongly linked to higher body mass, and glycemic control. Gut-derived 5-HT is likely to be an important driver of pathogenesis in human obesity and dysglycemia Refereed/Peer-reviewed

Precise identification of drinking and smoking patterns during pregnancy is crucial to better understand the risk to the fetus. The purpose of this manuscript is to describe the methodological approach used to define prenatal drinking and smoking trajectories from a large prospective pregnancy cohort, and to describe maternal characteristics associated with different exposure patterns. In the Safe Passage Study, detailed information regarding quantity, frequency, and timing of exposure was self-reported up to four times during pregnancy and at 1 month post-delivery. Exposure trajectories were developed using data from 11,692 pregnancies (9,912 women) where pregnancy outcome was known. Women were from three diverse populations: white (23%) and American Indian (17%) in the Northern Plains, US, and mixed ancestry (59%) in South Africa (other/not specified [1%]). Group-based trajectory modeling was used to identify 5 unique drinking trajectories (1 none/minimal, 2 quitting groups, 2 continuous groups) and 7 smoking trajectories (1 none/minimal, 2 quitting groups, 4 continuous groups). Women with pregnancies assigned to the low- or high-continuous drinking groups were less likely to have completed high school and were more likely to have enrolled in the study in the third trimester, be of mixed ancestry, or be depressed than those assigned to the none/minimal or quit-drinking groups. Results were similar when comparing continuous smokers to none/minimal and quit-smoking groups. Further, women classified as high- or low-continuous drinkers were more likely to smoke at moderate-, high-, and very high-continuous levels, as compared to women classified as non-drinkers and quitters. This is the first study of this size to utilize group-based trajectory modeling to identify unique prenatal drinking and smoking trajectories. These trajectories will be used in future analyses to determine which specific exposure patterns subsequently manifest as poor peri- and postnatal outcomes.

BackgroundAbout 15.4 million people in the UK live with a long-term condition. Of the health and social care spend, 70% is invested in caring for this population. Evidence suggests that group-work interventions offer patient support, improved outcomes, and reduce the costs of care.AimTo review the current evidence base examining the effectiveness of group work in long-term physical disease where such groups are facilitated by healthcare professionals.Design and settingSystematic review and narrative synthesis of studies of group-work interventions led by health professionals for adults with specified long-term illnesses.MethodMEDLINE, EMBASE, PsycINFO, and Cochrane databases were systematically searched using terms relating to group work and long-term conditions. Studies were included if they were randomised controlled trials (RCTs) with a control group that did not include group work.ResultsThe 14 included studies demonstrated a high degree of heterogeneity in terms of participant characteristics, interventions, and outcome measures and were of varying quality. The studies demonstrated some statistically significant improvements in pain, psychological outcomes, self-efficacy, self-care, and quality of life resulting from intervention.ConclusionThis review demonstrates significant benefits resulting from group participation, in adults with long-term disease. Results were mixed and some benefits were short-lived. Nevertheless, these results suggest that group work should be more widely used in the management and support of adults with long-term illness. There is a need for larger and better-quality studies to explore this potentially important area further.

Gut-derived serotonin (5-HT) is released from enterochromaffin (EC) cells in response to nutrient cues, and acts to slow gastric emptying and modulate gastric motility. Rodent studies also evidence a role for gut-derived 5-HT in the control of hepatic glucose production, lipolysis and thermogenesis, and in mediating diet-induced obesity. EC cell number and 5-HT content is increased in the small intestine of obese rodents and human, however, it is unknown whether EC cells respond directly to glucose in humans, and whether their capacity to release 5-HT is perturbed in obesity. We therefore investigated 5-HT release from human duodenal and colonic EC cells in response to glucose, sucrose, fructose and &alpha, glucoside (&alpha, MG) in relation to body mass index (BMI). EC cells released 5-HT only in response to 100 and 300 mM glucose (duodenum) and 300 mM glucose (colon), independently of osmolarity. Duodenal, but not colonic, EC cells also released 5-HT in response to sucrose and &alpha, MG, but did not respond to fructose. 5-HT content was similar in all EC cells in males, and colonic EC cells in females, but 3 to 4-fold higher in duodenal EC cells from overweight females (p &lt, 0.05 compared to lean, obese). Glucose-evoked 5-HT release was 3-fold higher in the duodenum of overweight females (p &lt, 0.05, compared to obese), but absent here in overweight males. Our data demonstrate that primary human EC cells respond directly to dietary glucose cues, with regional differences in selectivity for other sugars. Augmented glucose-evoked 5-HT release from duodenal EC is a feature of overweight females, and may be an early determinant of obesity.

This chapter aims to show that sex research is no more neutral than any other body of knowledge, and to challenge the claim that it promotes women’s liberation. It argues that the ‘scientific’ model of male sexuality is little more than a legitimation of the form of male sexuality which exists under, and is central to, male supremacy; and that in constructing this form of sexuality as ‘natural’ and ‘universal’, the sex researchers are strongly implicated in the maintenance and reproduction of male supremacy. Two of the most fundamental assumptions of sexology are that heterosexuality is natural and that the most natural form of heterosexual activity is coitus, that is, penetration of the vagina by the penis. The primacy of heterosexuality, and of penetration, in the sexologists’ model of sexuality can be partly explained by the fact that it is basically a biological model, within which sex is conceptualized as an ultimately reproductive function, a function necessary to life itself.

Aim To evaluate safety, tolerability and pharmacokinetics of oral PF-05190457, an oral ghrelin receptor inverse agonist, in healthy adults. Methods Single (SAD) and multiple ascending dose (MAD) studies were randomised, placebo-controlled, double-blind studies. Thirty-five healthy men (age 38.2 ± 10.4 years; body mass index 24.8 ± 3.1 kg m–2 [mean ± standard deviation]) received ≥1 dose (2, 10, 40 [divided], 50, 100, 150, and 300 [single or divided] mg) of PF-05190457 and/or placebo in the SAD. In the MAD study, 35 healthy men (age 39.7 ± 10.1 years; body mass index 25.9 ± 3.3 kg m–2) received ≥1 dose (2, 10, 40 and 100 mg twice daily) of PF-05190457 and/or placebo daily for 2 weeks. Results PF-05190457 absorption was rapid with a Tmax of 0.5–3 hours and a half-life between 8.2–9.8 hours. PF-05190457 dose-dependently blocked ghrelin (1 pmol kg–1 min–1)-induced growth hormone (GH) release with (mean [90% confidence interval]) 77% [63–85%] inhibition at 100 mg. PF-05190457 (150 mg) delayed gastric emptying lag time by 30% [7–58%] and half emptying time by 20% [7–35%] with a corresponding decrease in postprandial glucose by 9 mg dL–1. The most frequent adverse event reported by 30 subjects at doses ≥50 mg was somnolence. PF-05190457 plasma concentrations also increased heart rate up to 13.4 [4.8–58.2] beats min–1 and, similar to the effect on glucose and ghrelin-induced GH, was lost within 2 weeks. Conclusions PF-05190457 is a well-tolerated first-in-class ghrelin receptor inverse agonist with acceptable pharmacokinetics for oral daily dosing. Blocking ghrelin receptors inhibits ghrelin-induced GH, and increases heart rate, effects that underwent tachyphylaxis with chronic dosing. PF-051940457 has the potential to treat centrally-acting disorders such as insomnia.

Purpose Most people with epilepsy (PWE) in low-income countries are not treated. We identified risk factors for the epilepsy treatment gap in rural Tanzania. Methods We identified adult PWE in a community-based prevalence study. Factors associated with failure to access or default from medical care were identified using logistic regression modelling. Results A total of 291 PWE were included, of whom 253 (86.9%) had presented to medical services. Failure to present was positively associated with using alcohol (odds ratio (OR) 4.20; 95% confidence interval (CI) 1.63 to 10.82) or attending traditional healers (OR 2.62; CI 1.00 to 6.83) and inversely associated with having completed primary education (OR 0.33; CI 0.11 to 0.96). Default from treatment was associated with being male (OR 3.35; CI 1.39 to 8.09), having a seizure-related injury (OR 2.64; CI 1.12 to 6.19), believing in a supernatural cause for epilepsy (OR 5.44; CI 1.48 to 19.94) or having no expressed knowledge of cause (OR 5.29; CI 1.60 to 17.52). Cases less likely to default had a duration of epilepsy greater than 10 years (OR 0.28; CI 0.09 to 0.90) or had previously received a seizure-related diagnosis (OR 0.25; CI 0.09 to 0.65). Of all 291 PWE included, 118 denied taking AEDs; the epilepsy treatment gap in this population was therefore 40.5% (95% CI 34.9 to 46.2). Conclusion Interventions to improve access to education and to support formal diagnoses may promote access to, and retention under, medical care for PWE in rural Tanzania and in other low-income countries.

This article presents findings related to the role parents can play in the prevention of cyberbullying and the promotion of cyber-kindness. The findings are drawn from a study conducted at a private school in Western Canada, involving 177 student survey participants in Grades 8 through 10 (including both day students and boarding students) and interviews with 15 educators employed at the same school. Findings relate to parental supervision of computer usage, students&rsquo, willingness to inform parents about cyberbullying, and how students and educators view the role of parents in relation to the prevention of cyberbullying and the promotion of cyber-kindness. Education, dialogue, relationship strengthening, computer usage monitoring, and partnerships between schools and parents are emphasized as solutions, which are highly consistent with the existing research literature on this topic. Additionally, the study reveals the particular vulnerability of boarding students to cyberbullying victimization and perpetration.

This chapter offers a gendered analysis of experiences with cyberbullying reported by university students and faculty based on the power dynamics that characterize the post-secondary context. The gender differences that emerge help to carve out a clearer understanding about cyberbullying behaviour at the university level. A number of theoretical frameworks have attempted to account for gender differences with respect to cyberbullying. Work on gender and cyberbullying in elementary and secondary schools has adopted the frames of relational aggression for girls and cognitive and affective deficits for boys. The chapter briefly outlines the methods employed in examination of cyberbullying among post-secondary students and faculty, followed by a summary of the findings, and their analysis in relation to the lens of power. Cyberbullying is inscribed within the context and may merely be the newest manifestation of power relations and gender inequality in the post-secondary context.

BACKGROUND Adaptive coping behaviors can improve well-being for young people experiencing life stressors, while maladaptive coping can increase vulnerability to mental health problems in youth and into adulthood. Young people could potentially benefit from the use of digital technology tools to enhance their coping skills and overcome barriers in help-seeking behaviors. However, little is known about the desired digital technology use for self-management of well-being among young people in the general population. OBJECTIVE This is a small, qualitative study aimed at exploring what young people desire from digital technology tools for the self-management of their well-being. METHODS Young people aged 12-18 years were recruited from the general community to take part in semistructured interviews. Recorded data from the interviews were transcribed and analyzed using inductive thematic analysis. RESULTS In total, 14 participants were recruited and completed the study, with a mean age of 14.6 years (female n=3). None of the participants reported using any digital tools specifically designed to manage well-being. However, as indicated through the emerged themes, young people used digital technology to reduce their stress levels and manage their mood, mainly through games, music, and videos. Overall, identified themes showed that young people were keen on using such tools and desired certain facets and features of an ideal tool for self-management of well-being. Themes related to these facets indicated what young people felt a tool should do to improve well-being, including being immersed in a stress-free environment, being uplifting, and that such a tool would direct them to resources based on their needs. The feature-based themes suggested that young people wanted the tool to be flexible and enable engagement with others while also being sensitive to privacy. CONCLUSIONS The young people interviewed in this study did not report engaging with digital technology specialized to improving well-being but instead used media already accessed in their daily lives in order to self-manage their psychological states. As a result, the variety of coping strategies reported and digital tools used was limited to the resources that were already being used for recreational and social purposes. These findings contribute to the scarce research into young people’s preferred use of digital technology tools for the self-management of their well-being. However, this was a small-scale study and the current participant sample is not representative of the general youth population. Therefore, the results are only tentative and warrant further investigation.