In Infancy, It’s the Extremes of Arousal That Are ‘Sticky’: Naturalistic Data Challenge Purely Homeostatic Approaches to Studying Self-Regulation

Most theoretical models of arousal/regulatory function emphasise the maintenance of homeostasis; consistent with this, most previous research into arousal has concentrated on examining individuals’ recovery following the administration of experimentally administered stressors. Here, we take a different approach: we recorded day-long spontaneous fluctuations in autonomic arousal (indexed via electrocardiogram, heart rate variability and actigraphy) in a cohort of 82 typically developing 12-month-old infants while they were at home and awake. Based on the aforementioned models, we hypothesised that extreme high or low arousal states might be more short-lived than intermediate arousal states. Our results suggested that, contrary to this, both low- and high-arousal states were more persistent than intermediate arousal states. The same pattern was present when the data were viewed over multiple epoch sizes from 1 second to 5 minutes; over 10-15-minute time-scales, high-arousal states were more persistent than low- and intermediate states. One possible explanation for these findings is that extreme arousal states have intrinsically greater hysteresis; another is that, through ‘metastatic’ processes, small initial increases and decreases in arousal can become progressively amplified over time. Rather than exclusively studying recovery, we argue that future research into self regulation during early childhood should instead examine the mechanisms through which some states can be maintained, or even amplified, over time

Parents mimic and influence their infant’s autonomic state through dynamic affective state matching

When we see someone experiencing an emotion, and when we experience it ourselves, common neurophysiological activity occurs [1, 2]. But although inter-dyadic synchrony, concurrent and sequential [3], has been identified, its functional significance remains inadequately understood. Specifically, how do influences of partner A on partner B reciprocally influence partner A? For example, if I am experiencing an affective state and someone matches their physiological state to mine, what influence does this have on me – the person experiencing the emotion? Here, we investigated this using infant-parent dyads. We developed miniaturised microphones to record spontaneous vocalisations and wireless autonomic monitors to record heart rate, heart rate variability and movement in infants and parents concurrently in naturalistic settings. Overall, we found that infant-parent autonomic activity did not covary across the day – but that ‘high points’ of infant arousal led to autonomic changes in the parent, and that instances where the adult showed greater autonomic responsivity were associated with faster infant quieting. Parental responsivity was higher following peaks in infant negative affect than in positive affect. Overall, parents responded to increases in their child’s arousal by increasing their own. However, when the overall arousal level of the dyad was high, parents responded to elevated child arousal by decreasing their own arousal. Our findings suggest that autonomic state matching has a direct effect on the person experiencing the affective state, and that parental co-regulation may involve both connecting, and disconnecting, their own arousal state from that of the child contingent on context

Influences of environmental stressors on autonomic function in 12-month-old infants: understanding early common pathways to atypical emotion regulation and cognitive performance

Background Previous research has suggested that children exposed to more early‐life stress show worse mental health outcomes and impaired cognitive performance in later life, but the mechanisms subserving these relationships remain poorly understood. Method Using miniaturised microphones and physiological arousal monitors (electrocardiography, heart rate variability and actigraphy), we examined for the first time infants’ autonomic reactions to environmental stressors (noise) in the home environment, in a sample of 82 12‐month‐old infants from mixed demographic backgrounds. The same infants also attended a laboratory testing battery where attention‐ and emotion‐eliciting stimuli were presented. We examined how children's environmental noise exposure levels at home related to their autonomic reactivity and to their behavioural performance in the laboratory. Results Individual differences in total noise exposure were independent of other socioeconomic and parenting variables. Children exposed to higher and more rapidly fluctuating environmental noise showed more unstable autonomic arousal patterns overall in home settings. In the laboratory testing battery, this group showed more labile and short‐lived autonomic changes in response to novel attention‐eliciting stimuli, along with reduced visual sustained attention. They also showed increased arousal lability in response to an emotional stressor. Conclusions Our results offer new insights into the mechanisms by which environmental noise exposure may confer increased risk of adverse mental health and impaired cognitive performance during later life

Virtual screening for inhibitors of the human TSLP:TSLPR interaction

The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) plays a pivotal role in the pathophysiology of various allergy disorders that are mediated by type 2 helper T cell (Th2) responses, such as asthma and atopic dermatitis. TSLP forms a ternary complex with the TSLP receptor (TSLPR) and the interleukin-7-receptor subunit alpha (IL-7Ra), thereby activating a signaling cascade that culminates in the release of pro-inflammatory mediators. In this study, we conducted an in silico characterization of the TSLP: TSLPR complex to investigate the drugability of this complex. Two commercially available fragment libraries were screened computationally for possible inhibitors and a selection of fragments was subsequently tested in vitro. The screening setup consisted of two orthogonal assays measuring TSLP binding to TSLPR: a BLI-based assay and a biochemical assay based on a TSLP: alkaline phosphatase fusion protein. Four fragments pertaining to diverse chemical classes were identified to reduce TSLP: TSLPR complex formation to less than 75% in millimolar concentrations. We have used unbiased molecular dynamics simulations to develop a Markov state model that characterized the binding pathway of the most interesting compound. This work provides a proof-ofprinciple for use of fragments in the inhibition of TSLP: TSLPR complexation

Entropic Tension in Crowded Membranes

Unlike their model membrane counterparts, biological membranes are richly decorated with a heterogeneous assembly of membrane proteins. These proteins are so tightly packed that their excluded area interactions can alter the free energy landscape controlling the conformational transitions suffered by such proteins. For membrane channels, this effect can alter the critical membrane tension at which they undergo a transition from a closed to an open state, and therefore influence protein function \emph{in vivo}. Despite their obvious importance, crowding phenomena in membranes are much less well studied than in the cytoplasm. Using statistical mechanics results for hard disk liquids, we show that crowding induces an entropic tension in the membrane, which influences transitions that alter the projected area and circumference of a membrane protein. As a specific case study in this effect, we consider the impact of crowding on the gating properties of bacterial mechanosensitive membrane channels, which are thought to confer osmoprotection when these cells are subjected to osmotic shock. We find that crowding can alter the gating energies by more than $2\;k_BT$ in physiological conditions, a substantial fraction of the total gating energies in some cases. Given the ubiquity of membrane crowding, the nonspecific nature of excluded volume interactions, and the fact that the function of many membrane proteins involve significant conformational changes, this specific case study highlights a general aspect in the function of membrane proteins.Comment: 20 pages (inclduing supporting information), 4 figures, to appear in PLoS Comp. Bio

Ligand-Receptor Interactions

The formation and dissociation of specific noncovalent interactions between a variety of macromolecules play a crucial role in the function of biological systems. During the last few years, three main lines of research led to a dramatic improvement of our understanding of these important phenomena. First, combination of genetic engineering and X ray cristallography made available a simultaneous knowledg of the precise structure and affinity of series or related ligand-receptor systems differing by a few well-defined atoms. Second, improvement of computer power and simulation techniques allowed extended exploration of the interaction of realistic macromolecules. Third, simultaneous development of a variety of techniques based on atomic force microscopy, hydrodynamic flow, biomembrane probes, optical tweezers, magnetic fields or flexible transducers yielded direct experimental information of the behavior of single ligand receptor bonds. At the same time, investigation of well defined cellular models raised the interest of biologists to the kinetic and mechanical properties of cell membrane receptors. The aim of this review is to give a description of these advances that benefitted from a largely multidisciplinar approach

Protein binding hot spots and the residue-residue pairing preference: a water exclusion perspective

<p>Abstract</p> <p>Background</p> <p>A protein binding hot spot is a small cluster of residues tightly packed at the center of the interface between two interacting proteins. Though a hot spot constitutes a small fraction of the interface, it is vital to the stability of protein complexes. Recently, there are a series of hypotheses proposed to characterize binding hot spots, including the pioneering O-ring theory, the insightful 'coupling' and 'hot region' principle, and our 'double water exclusion' (DWE) hypothesis. As the perspective changes from the O-ring theory to the DWE hypothesis, we examine the physicochemical properties of the binding hot spots under the new hypothesis and compare with those under the O-ring theory.</p> <p>Results</p> <p>The requirements for a cluster of residues to form a hot spot under the DWE hypothesis can be mathematically satisfied by a biclique subgraph if a vertex is used to represent a residue, an edge to indicate a close distance between two residues, and a bipartite graph to represent a pair of interacting proteins. We term these hot spots as DWE bicliques. We identified DWE bicliques from crystal packing contacts, obligate and non-obligate interactions. Our comparative study revealed that there are abundant <it>unique </it>bicliques to the biological interactions, indicating specific biological binding behaviors in contrast to crystal packing. The two sub-types of biological interactions also have their own signature bicliques. In our analysis on residue compositions and residue pairing preferences in DWE bicliques, the focus was on interaction-preferred residues (ipRs) and interaction-preferred residue pairs (ipRPs). It is observed that hydrophobic residues are heavily involved in the ipRs and ipRPs of the obligate interactions; and that aromatic residues are in favor in the ipRs and ipRPs of the biological interactions, especially in those of the non-obligate interactions. In contrast, the ipRs and ipRPs in crystal packing are dominated by hydrophilic residues, and most of the anti-ipRs of crystal packing are the ipRs of the obligate or non-obligate interactions.</p> <p>Conclusions</p> <p>These ipRs and ipRPs in our DWE bicliques describe a diverse binding features among the three types of interactions. They also highlight the specific binding behaviors of the biological interactions, sharply differing from the artifact interfaces in the crystal packing. It can be noted that DWE bicliques, especially the unique bicliques, can capture deep insights into the binding characteristics of protein interfaces.</p

A Common Model for Cytokine Receptor Activation: Combined Scissor-Like Rotation and Self-Rotation of Receptor Dimer Induced by Class I Cytokine

The precise mechanism by which the binding of a class I cytokine to the extracellular domain of its corresponding receptor transmits a signal through the cell membrane remains unclear. Receptor activation involves a cytokine-receptor complex with a 1∶2 stoichiometry. Previously we used our transient-complex theory to calculate the rate constant of the initial cytokine-receptor binding to form a 1∶1 complex. Here we computed the binding pathway leading to the 1∶2 activation complex. Three cytokine systems (growth hormone, erythropoietin, and prolactin) were studied, and the focus was on the binding of the extracellular domain of the second receptor molecule after forming the 1∶1 complex. According to the transient-complex theory, translational and rotation diffusion of the binding entities bring them together to form a transient complex, which has near-native relative separation and orientation but not the short-range specific native interactions. Subsequently conformational rearrangement leads to the formation of the native complex. We found that the changes in relative orientations between the two receptor molecules from the transient complex to the 1∶2 native complex are similar for the three cytokine-receptor systems. We thus propose a common model for receptor activation by class I cytokines, involving combined scissor-like rotation and self-rotation of the two receptor molecules. Both types of rotations seem essential: the scissor-like rotation separates the intracellular domains of the two receptor molecules to make room for the associated Janus kinase molecules, while the self-rotation allows them to orient properly for transphosphorylation. This activation model explains a host of experimental observations. The transient-complex based approach presented here may provide a strategy for designing antagonists and prove useful for elucidating activation mechanisms of other receptors

Integrating water exclusion theory into βcontacts to predict binding free energy changes and binding hot spots

10.1186/1471-2105-15-57BMC Bioinformatics151-BBMI