G-protein-coupled receptors are membrane proteins that are regulated by a small family of arrestin proteins. During formation of the arrestin-receptor complex, arrestin first interacts with the ...phosphorylated receptor C terminus in a pre-complex, which activates arrestin for tight receptor binding. Currently, little is known about the structure of the pre-complex and its transition to a high-affinity complex. Here we present molecular dynamics simulations and site-directed fluorescence experiments on arrestin-1 interactions with rhodopsin, showing that loops within the C-edge of arrestin function as a membrane anchor. Activation of arrestin by receptor-attached phosphates is necessary for C-edge engagement of the membrane, and we show that these interactions are distinct in the pre-complex and high-affinity complex in regard to their conformation and orientation. Our results expand current knowledge of C-edge structure and further illuminate the conformational transitions that occur in arrestin along the pathway to tight receptor binding.
Despite intense interest in discovering drugs that cause G-protein-coupled receptors (GPCRs) to selectively stimulate or block arrestin signalling, the structural mechanism of receptor-mediated ...arrestin activation remains unclear
. Here we reveal this mechanism through extensive atomic-level simulations of arrestin. We find that the receptor's transmembrane core and cytoplasmic tail-which bind distinct surfaces on arrestin-can each independently stimulate arrestin activation. We confirm this unanticipated role of the receptor core, and the allosteric coupling between these distant surfaces of arrestin, using site-directed fluorescence spectroscopy. The effect of the receptor core on arrestin conformation is mediated primarily by interactions of the intracellular loops of the receptor with the arrestin body, rather than the marked finger-loop rearrangement that is observed upon receptor binding. In the absence of a receptor, arrestin frequently adopts active conformations when its own C-terminal tail is disengaged, which may explain why certain arrestins remain active long after receptor dissociation. Our results, which suggest that diverse receptor binding modes can activate arrestin, provide a structural foundation for the design of functionally selective ('biased') GPCR-targeted ligands with desired effects on arrestin signalling.
People regularly make decisions that are not aligned with their own self-interests. These irrational decisions often stem from humans having bounded rationality (e.g., limited computational power), ...which produces reliable cognitive biases that occur outside of people’s awareness and influences the decisions people make. There are many important decisions leading up to a suicide attempt, and it is likely that these same biases exist within suicide-related decisions. This article presents an argument for the likely existence of cognitive biases within suicide-related decision making and how they may influence people to make irrational decisions. In addition, this article provides new evidence for using a behavioral economic intervention—nudges—as a potential way to combat rising suicide rates. We explore how nudges can help increase means safety, disseminate suicide prevention skills/materials, diminish well-known biases (e.g., confirmation bias), and uncover biases that may be occurring when making suicide-related decisions.
Introduction
Contemporary models of suicide have largely overlooked why a person at high risk for suicide attempts suicide at a specific time. We propose the construct of unacceptable loss thresholds ...(i.e., a person’s tolerance limit for a negative life event, which if violated results in an increase in suicide risk), which addresses many paradoxes in the literature related to suicide triggers. The aim of this paper is to provide preliminary proof of concept and to stimulate replication and further empirical study.
Methods
We recruited an online community sample of individuals with a suicide attempt history (n = 144). These individuals answered questions about the time leading up to their most recent suicide attempt.
Results
The majority (70.8% yes; 18.1% cannot remember; 11.1% no) reported creating a threshold of unacceptable loss, and that relatively small events were enough to trigger feelings that life was not worth living (63.9% yes; 30.6% maybe; 5.6% no). Further, the majority (57.6% yes; 21.5% yes, but only if asked; 20.8% ‐ no) reported they would be willing to tell their therapist/doctor about their thresholds of unacceptable loss.
Conclusion
The construct of unacceptable loss deserves further empirical inquiry. Individuals contemplating suicide set them and if the loss occurs, it may trigger suicidal action in suicide ready individuals. Thresholds could provide risk assessment and safety planning data currently being overlooked.
Understanding how individuals integrate new information to form beliefs under changing emotional conditions is crucial to describing decision-making processes. Previous research suggests that ...although most people demonstrate bias toward optimistic appraisals of new information when updating beliefs, individuals with dysphoric psychiatric conditions (e.g., major depression) do not demonstrate this same bias. Despite these findings, limited research has investigated the relationship between affective states and belief updating processes.BACKGROUND AND OBJECTIVESUnderstanding how individuals integrate new information to form beliefs under changing emotional conditions is crucial to describing decision-making processes. Previous research suggests that although most people demonstrate bias toward optimistic appraisals of new information when updating beliefs, individuals with dysphoric psychiatric conditions (e.g., major depression) do not demonstrate this same bias. Despite these findings, limited research has investigated the relationship between affective states and belief updating processes.We induced neutral and sad moods in participants and had them complete a belief-updating paradigm by estimating the likelihood of negative future events happening to them, viewing the actual likelihood, and then re-estimating their perceived likelihood.METHODSWe induced neutral and sad moods in participants and had them complete a belief-updating paradigm by estimating the likelihood of negative future events happening to them, viewing the actual likelihood, and then re-estimating their perceived likelihood.We observed that individuals updated their beliefs more after receiving desirable information relative to undesirable information under neutral conditions. Further, we found that individuals did not demonstrate unrealistic optimism under negative affective conditions.RESULTSWe observed that individuals updated their beliefs more after receiving desirable information relative to undesirable information under neutral conditions. Further, we found that individuals did not demonstrate unrealistic optimism under negative affective conditions.This study incorporated a population of university students under laboratory conditions and would benefit from replication and extension in clinical populations and naturalistic settings.LIMITATIONSThis study incorporated a population of university students under laboratory conditions and would benefit from replication and extension in clinical populations and naturalistic settings.These findings suggest that momentary fluctuations in mood affect how individuals integrate information to form beliefs.CONCLUSIONSThese findings suggest that momentary fluctuations in mood affect how individuals integrate information to form beliefs.
Background
Concussions are associated with a variety of physical, cognitive, and mental health impairments. If sustained during adolescence, a time when the brain is undergoing development, the risk ...of long‐term impairments becomes heightened. This is a notable subject for investigation as many concussions are sustained among adolescents during high school sports and other physical activities.
Methods
We used data from the 2019 United States Youth Risk Behavior Survey to investigate the association between concussions and suicidality (i.e., suicide ideation, planning, and attempts), suicide capability (i.e., physical fighting and weapon carrying), and hopelessness, a risk factor for suicide. We utilized a cross‐sectional design and used multivariate regression models and t tests for analysis.
Results
Participants were 1754 adolescent students who sustained a concussion during the prior year (54.61% male; M age = 15.94) and 9795 adolescent students who did not sustain a concussion during the prior year (47.27% male; M age = 15.95). Females were less likely (13.23%) than males (17.12%) to report at least one concussion in the past 12 months. Both male and female students who had experienced a concussion were more likely to report physical fighting, weapon carrying, and hopelessness. Male students with a concussion history were also more likely to report suicide attempts than male students without a concussion history.
Conclusion
Findings indicate that concussions are associated with an increased risk of suicide attempts, suicide capability, and hopelessness among male adolescents and suicide capability and hopelessness among female adolescents. They further suggest a need for additional mental health support and safety policies for student‐athletes and other at‐risk adolescents.
Nocturnal panic refers to waking in a state of panic without obvious triggers, experiencing the same symptoms as panic attacks that occur while awake. Interrelationships between daytime and nocturnal ...panic symptoms have not been examined despite theories suggesting panic symptoms perpetuate one another in a forward feedback loop. The current study compared associations between symptoms in daytime and nocturnal panic using network analysis. Network theory conceptualizes symptoms as causing one another, rather than originating from a latent variable (i.e., a disorder). Given that nocturnal panic originates from sleep stages without cognitive activity, cognitive symptoms were expected to be more central in daytime panic networks than nocturnal panic networks. Prior literature indicates similar nocturnal and daytime panic severity; thus, we expected that panic groups would report equivalent panic symptom severity. An online community sample (N = 215) provided panic symptom history. Panic network structures did not differ, although the daytime panic network produced stronger and more numerous connections between physical and cognitive symptoms. The nocturnal panic group, however, reported more severe cognitive symptoms than the daytime panic group. These results challenge biologically-focused nocturnal panic theories and suggest a more significant role of cognitive symptoms in perpetuating nocturnal panic attacks once the individual awakens.
•Daytime and nocturnal panic network structures did not significantly differ.•Daytime network showed stronger connections between physical and cognitive symptoms.•Nocturnal panic group rated cognitive symptoms more severe than daytime panic group.
Exploring the scope and structure of suicide capability Shahnaz, Arezoo; Bauer, Brian W.; Daruwala, Samantha E. ...
Suicide & life-threatening behavior,
December 2020, 2020-12-00, 20201201, Volume:
50, Issue:
6
Journal Article
Objective
Recent theories of suicide suggest that a construct called “capability for suicide” facilitates the progression from suicidal thoughts to attempts. Various measures of capability have been ...developed to assess different parts of the construct, but studies report inconsistent findings regarding reliability, validity, and structure. The present study pooled items from multiple measures to identify distinct, reliable, and valid domains of suicide capability.
Method
We administered items from several suicide capability measures to an online sample of US adults (n = 387), and utilized exploratory factor analysis to identify distinct domains of capability. We then examined the internal consistencies of and intercorrelations among these domains, as well as their associations with suicide attempts.
Results
Findings identified three domains of suicide capability: fearlessness about death, practical capability, and pain tolerance. These domains were internally consistent (αs = 0.80–0.92), and relatively independent from one another (intercorrelations = 0.15–0.35). Finally, each of these domains was moderately elevated among attempters compared to ideators (although only fearlessness about death and practical capability offered unique information about attempter status).
Conclusions
Findings suggest that fearlessness about death, practical capability, and pain tolerance can be measured reliably, and may be relevant for understanding which ideators make attempts.
Cellular functions of arrestins are determined in part by the pattern of phosphorylation on the G protein-coupled receptors (GPCRs) to which arrestins bind. Despite high-resolution structural data of ...arrestins bound to phosphorylated receptor C-termini, the functional role of each phosphorylation site remains obscure. Here, we employ a library of synthetic phosphopeptide analogues of the GPCR rhodopsin C-terminus and determine the ability of these peptides to bind and activate arrestins using a variety of biochemical and biophysical methods. We further characterize how these peptides modulate the conformation of arrestin-1 by nuclear magnetic resonance (NMR). Our results indicate different functional classes of phosphorylation sites: 'key sites' required for arrestin binding and activation, an 'inhibitory site' that abrogates arrestin binding, and 'modulator sites' that influence the global conformation of arrestin. These functional motifs allow a better understanding of how different GPCR phosphorylation patterns might control how arrestin functions in the cell.
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