The mechanism of MinD stability modulation by MinE in Min protein dynamics

The patterns formed both in vivo and in vitro by the Min protein system have attracted much interest because of the complexity of their dynamic interactions given the apparent simplicity of the component parts. Despite both the experimental and theoretical attention paid to this system, the details of the biochemical interactions of MinD and MinE, the proteins responsible for the patterning, are still unclear. For example, no model consistent with the known biochemistry has yet accounted for the observed dual role of MinE in the membrane stability of MinD. Until now, a statistical comparison of models to the time course of Min protein concentrations on the membrane has not been carried out. Such an approach is a powerful way to test existing and novel models that are difficult to test using a purely experimental approach. Here, we extract time series from previously published fluorescence microscopy time lapse images of in vitro experiments and fit two previously described and one novel mathematical model to the data. We find that the novel model, which we call the Asymmetric Activation with Bridged Stability Model, fits the time-course data best. It is also consistent with known biochemistry and explains the dual MinE role via MinE-dependent membrane stability that transitions under the influence of rising MinE to membrane instability with positive feedback. Our results reveal a more complex network of interactions between MinD and MinE underlying Min-system dynamics than previously considered.

activin-2 is required for regeneration of polarity on the planarian anterior-posterior axis

Planarians are flatworms and can perform whole-body regeneration. This ability involves a mechanism to distinguish between anterior-facing wounds that require head regeneration and posterior-facing wounds that require tail regeneration. How this head-tail regeneration polarity decision is made is studied to identify principles underlying tissue-identity specification in regeneration. We report that inhibition of activin-2, which encodes an Activin-like signaling ligand, resulted in the regeneration of ectopic posterior-facing heads following amputation. During tissue turnover in uninjured planarians, positional information is constitutively expressed in muscle to maintain proper patterning. Positional information includes Wnts expressed in the posterior and Wnt antagonists expressed in the anterior. Upon amputation, several wound-induced genes promote re-establishment of positional information. The head-versus-tail regeneration decision involves preferential wound induction of the Wnt antagonist notum at anterior-facing over posterior-facing wounds. Asymmetric activation of notum represents the earliest known molecular distinction between head and tail regeneration, yet how it occurs is unknown. activin-2 RNAi animals displayed symmetric wound-induced activation of notum at anterior- and posterior-facing wounds, providing a molecular explanation for their ectopic posterior-head phenotype. activin-2 RNAi animals also displayed anterior-posterior (AP) axis splitting, with two heads appearing in anterior blastemas, and various combinations of heads and tails appearing in posterior blastemas. This was associated with ectopic nucleation of anterior poles, which are head-tip muscle cells that facilitate AP and medial-lateral (ML) pattern at posterior-facing wounds. These findings reveal a role for Activin signaling in determining the outcome of AP-axis-patterning events that are specific to regeneration.

Asymmetric opening of the homopentameric 5-HT3A serotonin receptor in lipid bilayers

Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop receptor family are key players in fast signal transduction throughout the nervous system. They have been shown to be modulated by the lipid environment, however the underlying mechanism is not well understood. We report three structures of the Cys-loop 5-HT3A serotonin receptor (5HT3R) reconstituted into saposin-based lipid bilayer discs: a symmetric and an asymmetric apo state, and an asymmetric agonist-bound state. In comparison to previously published 5HT3R conformations in detergent, the lipid bilayer stabilises the receptor in a more tightly packed, ‘coupled’ state, involving a cluster of highly conserved residues. In consequence, the agonist-bound receptor conformation adopts a wide-open pore capable of conducting sodium ions in unbiased molecular dynamics (MD) simulations. Taken together, we provide a structural basis for the modulation of 5HT3R by the membrane environment, and a model for asymmetric activation of the receptor.

A new asymmetric activation strategy for hydrazones as acyl anion equivalents in the bimetallic catalyzed carbonyl-ene reaction

A new asymmetric activation strategy for hydrazones as acyl anion equivalents in the dinuclear zinc cooperative catalyzed carbonyl-ene reaction was developed.

Multielectrode Cortical Stimulation Selectively Induces Unidirectional Wave Propagation in Biophysical/Neural Model

ABSTRACTCortical stimulation is emerging as an experimental tool in basic research and a promising therapy for a range of neuropsychiatric conditions. As multielectrode arrays enter clinical practice, the possibility of using spatiotemporal patterns of electrical stimulation to induce desired physiological patterns has become theoretically possible, but in practice can only be implemented by trial-and-error because of a lack of predictive models. Experimental evidence increasingly establishes travelling waves as fundamental to cortical information-processing, but we lack understanding how to control wave properties despite rapidly improving technologies. This study uses a hybrid biophysical-anatomical and neural-computational model to predict and understand how a simple pattern of cortical surface stimulation could induce directional traveling waves in excitatory cells via asymmetric activation of inhibitory cells. The ability to induce such activity via stimulation suggests the potential to treat a broad range of cognitive disorders and to shed light on the electrical nature of cortical functioning.

Beyond synchrony: the capacity of fMRI hyperscanning for the study of human social interaction

Hyperscanning—simultaneous brain scanning of two or more individuals—holds great promise in elucidating the neurobiological underpinnings of social cognitive functions. This article focuses on functional magnetic resonance imaging (fMRI) hyperscanning and identifies promising targets for studying the neuroscience of social interaction with fMRI hyperscanning. Specifically, we present applications of fMRI hyperscanning in the study of social interaction along with promising analysis approaches for fMRI hyperscanning, with its high spatial and low temporal resolution. We first review fMRI hyperscanning studies in social neuroscience and evaluate the premise of using this costly neuroimaging paradigm. Many second-person social neuroscience studies are possible without fMRI hyperscanning. However, certain fundamental aspects of social cognition in real-life social interactions, including different roles of interactors, shared intention emerging through interaction and history of interaction, can be addressed only with hyperscanning. We argue that these fundamental aspects have not often been investigated in fMRI hyperscanning studies. We then discuss the implication of the signal coupling found in fMRI hyperscanning and consider analysis approaches that make fair use of it. With fMRI hyperscanning, we can explore not only synchronous brain activations but whole-brain asymmetric activation patterns with a lagged association between interacting individuals.

A Zic2-regulated switch in a noncanonical Wnt/βcatenin pathway is essential for the formation of bilateral circuits

The Wnt pathway is involved in a wide array of biological processes during development and is deregulated in many pathological scenarios. In neurons, Wnt proteins promote both axon extension and repulsion, but the molecular mechanisms underlying these opposing axonal responses are unknown. Here, we show that Wnt5a is expressed at the optic chiasm midline and promotes the crossing of retinal axons by triggering an alternative Wnt pathway that depends on the accumulation of βcatenin but does not activate the canonical pathway. In ipsilateral neurons, the transcription factor Zic2 switches this alternative Wnt pathway by regulating the expression of a set of Wnt receptors and intracellular proteins. In combination with this alternative Wnt pathway, the asymmetric activation of EphB1 receptors at the midline phosphorylates βcatenin and elicits a repulsive response. This alternative Wnt pathway and its Zic2-triggered switch may operate in other contexts that require a two-way response to Wnt ligands.