Structure and dynamics of the active Gs-coupled human secretin receptor

The class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Molecular understanding of SecR binding and activation is important for its therapeutic exploitation. We combined cryo-electron microscopy, molecular dynamics, and biochemical cross-linking to determine a 2.3 Å structure, and interrogate dynamics, of secretin bound to the SecR:Gs complex. SecR exhibited a unique organization of its extracellular domain (ECD) relative to its 7-transmembrane (TM) core, forming more extended interactions than other family members. Numerous polar interactions formed between secretin and the receptor extracellular loops (ECLs) and TM helices. Cysteine-cross-linking, cryo-electron microscopy multivariate analysis and molecular dynamics simulations revealed that interactions between peptide and receptor were dynamic, and suggested a model for initial peptide engagement where early interactions between the far N-terminus of the peptide and SecR ECL2 likely occur following initial binding of the peptide C-terminus to the ECD

Conscious perception of errors and its relation to the anterior insula

To detect erroneous action outcomes is necessary for flexible adjustments and therefore a prerequisite of adaptive, goal-directed behavior. While performance monitoring has been studied intensively over two decades and a vast amount of knowledge on its functional neuroanatomy has been gathered, much less is known about conscious error perception, often referred to as error awareness. Here, we review and discuss the conditions under which error awareness occurs, its neural correlates and underlying functional neuroanatomy. We focus specifically on the anterior insula, which has been shown to be (a) reliably activated during performance monitoring and (b) modulated by error awareness. Anterior insular activity appears to be closely related to autonomic responses associated with consciously perceived errors, although the causality and directions of these relationships still needs to be unraveled. We discuss the role of the anterior insula in generating versus perceiving autonomic responses and as a key player in balancing effortful task-related and resting-state activity. We suggest that errors elicit reactions highly reminiscent of an orienting response and may thus induce the autonomic arousal needed to recruit the required mental and physical resources. We discuss the role of norepinephrine activity in eliciting sufficiently strong central and autonomic nervous responses enabling the necessary adaptation as well as conscious error perception

Resolution in electron tomography

Electron microscopes yield point resolution on the order of one angstrom, however the density maps from electron tomography typically have resolutions in the nanometre range. In this chapter I qualitatively discuss the typical limitations that occur in electron tomography of biological samples depending on the imaging modalities, with the focus on cryo electron tomography and subtomogram averaging

Heart work after errors: Behavioral adjustment following error commission involves cardiac effort

Posterror slowing (PES) is the observation that people respond slower on trials subsequent to error commissions than on trials subsequent to correct responses. Different accounts have been proposed to explain PES. On the one hand, it has been suggested that PES arises from an adaptive increase in cognitive control following error commission, thereby making people more cautious after making an error. On the other hand, PES has been attributed to an orienting response, indicating that attention is shifted toward the error. In the present study we tested these accounts by investigating the effects of error commission in both flanker and switch tasks on two task-evoked cardiac measures: the interbeat interval—that is, the interval between two consecutive R peaks—and the RZ interval—that is, the interval between the R peak and the Z point—as measured using electro- and impedance cardiography, respectively. These measures allowed us to measure cardiac deceleration (autonomic orienting) and cardiac effort mobilization, respectively. Our results revealed a shorter RZ interval during posterror trials, indicating increased effort mobilization following errors. In addition, we replicated earlier studies that have shown cardiac slowing during error trials. However, multilevel analyses showed that only the posterror decrease in RZ interval predicted posterror reaction times, whereas there was no positive relationship between error-related cardiac deceleration and posterror reaction times. Our results suggest that PES is related to increased cardiac effort, supporting a cognitive-control account of PES.Multivariate analysis of psychological dat

Grasping motor impairments in autism: Not action planning but movement execution is deficient

Contains fulltext : 125501.pdf (publisher's version ) (Closed access)Different views on the origin of deficits in action chaining in autism spectrum disorders (ASD) have been posited, ranging from functional impairments in action planning to internal models supporting motor control. Thirty-one children and adolescents with ASD and twenty-nine matched controls participated in a two-choice reach-to-grasp paradigm wherein participants received cueing information indicating either the object location or the required manner of grasping. A similar advantage for location cueing over grip cueing was found in both groups. Both accuracy and reaction times of the ASD group were indistinguishable from the control group. In contrast, movement times of the ASD group were significantly delayed in comparison with controls. These findings suggest that movement execution rather than action planning is deficient in ASD, and that deficits in action chaining derive from impairments in internal action models supporting action execution