Nonlinear electrochemical relaxation around conductors

We analyze the simplest problem of electrochemical relaxation in more than one dimension - the response of an uncharged, ideally polarizable metallic sphere (or cylinder) in a symmetric, binary electrolyte to a uniform electric field. In order to go beyond the circuit approximation for thin double layers, our analysis is based on the Poisson-Nernst-Planck (PNP) equations of dilute solution theory. Unlike most previous studies, however, we focus on the nonlinear regime, where the applied voltage across the conductor is larger than the thermal voltage. In such strong electric fields, the classical model predicts that the double layer adsorbs enough ions to produce bulk concentration gradients and surface conduction. Our analysis begins with a general derivation of surface conservation laws in the thin double-layer limit, which provide effective boundary conditions on the quasi-neutral bulk. We solve the resulting nonlinear partial differential equations numerically for strong fields and also perform a time-dependent asymptotic analysis for weaker fields, where bulk diffusion and surface conduction arise as first-order corrections. We also derive various dimensionless parameters comparing surface to bulk transport processes, which generalize the Bikerman-Dukhin number. Our results have basic relevance for double-layer charging dynamics and nonlinear electrokinetics in the ubiquitous PNP approximation.Comment: 25 pages, 17 figures, 4 table

A Single-Cell Model for Synaptic Transmission and Plasticity in Human iPSC-Derived Neurons

Synaptic dysfunction is associated with many brain disorders, but robust human cell models to study synaptic transmission and plasticity are lacking. Instead, current in vitro studies on human neurons typically rely on spontaneous synaptic events as a proxy for synapse function. Here, we describe a standardized in vitro approach using human neurons cultured individually on glia microdot arrays that allow single-cell analysis of synapse formation and function. We show that single glutamatergic or GABAergic forebrain neurons differentiated from human induced pluripotent stem cells form mature synapses that exhibit robust evoked synaptic transmission. These neurons show plasticity features such as synaptic facilitation, depression, and recovery. Finally, we show that spontaneous events are a poor predictor of synaptic maturity and do not correlate with the robustness of evoked responses. This methodology can be deployed directly to evaluate disease models for synaptic dysfunction and can be leveraged for drug development and precision medicine. This multisite study by Meijer et al. establishes a standardized in vitro approach to study synapse formation and function in single iPSC-derived human neurons. They validate this approach for GABA and glutamatergic human neurons. The methodology is scalable and suitable for compound screening and disease modeling

Inositol hexakisphosphate increases the size of platelet aggregates

The inositol phosphates, InsP5 and InsP6, have recently been identified as binding partners of fibrinogen, which is critically involved in hemostasis by crosslinking activated platelets at sites of vascular injury. Here, we investigated the putative physiological role of this interaction and found that platelets increase their InsP6 concentration upon stimulation with the PLC-activating agonists thrombin, collagen I and ADP and present a fraction of it at the outer plasma membrane. Cone and plate analysis in whole blood revealed that InsP6 specifically increases platelet aggregate size. This effect is fibrinogen-dependent, since it is inhibited by an antibody that blocks fibrinogen binding to platelets. Furthermore, InsP6 has only an effect on aggregate size of washed platelets when fibrinogen is present, while it has no influence in presence of von Willebrand factor or collagen. By employing blind docking studies we predicted the binding site for InsP6 at the bundle between the γ and β helical subunit of fibrinogen. Since InsP6 is unable to directly activate platelets and it did not exhibit an effect on thrombin formation or fibrin structure, our data indicate that InsP6 might be a hemostatic agent that is produced by platelets upon stimulation with PLC-activating agonists to promote platelet aggregation by supporting crosslinking of fibrinogen and activated platelets

Inositol hexakisphosphate increases the size of platelet aggregates

The inositol phosphates, InsP5 and InsP6, have recently been identified as binding partners of fibrinogen, which is critically involved in hemostasis by crosslinking activated platelets at sites of vascular injury. Here, we investigated the putative physiological role of this interaction and found that platelets increase their InsP6 concentration upon stimulation with the PLC-activating agonists thrombin, collagen I and ADP and present a fraction of it at the outer plasma membrane. Cone and plate analysis in whole blood revealed that InsP6 specifically increases platelet aggregate size. This effect is fibrinogen-dependent, since it is inhibited by an antibody that blocks fibrinogen binding to platelets. Furthermore, InsP6 has only an effect on aggregate size of washed platelets when fibrinogen is present, while it has no influence in presence of von Willebrand factor or collagen. By employing blind docking studies we predicted the binding site for InsP6 at the bundle between the γ and β helical subunit of fibrinogen. Since InsP6 is unable to directly activate platelets and it did not exhibit an effect on thrombin formation or fibrin structure, our data indicate that InsP6 might be a hemostatic agent that is produced by platelets upon stimulation with PLC-activating agonists to promote platelet aggregation by supporting crosslinking of fibrinogen and activated platelets