Molecular dynamics (MD) simulations were used to characterize the equilibrium size, shape, hydration, and self-assembly of dodecylphosphocholine (DPC) and dodecyl-β-D-maltoside (DDM) micelles. We show that DPC molecules self-assemble to form micelles with sizes within the range reported in the experimental literature. The equilibrium shape of DPC and DDM micelles as well as associated micellar radii are in agreement with small-angle X-ray scattering (SAXS) experiments and theoretical packing parameters. In addition, we show that hydration of the micelle interior is limited; however, flexibility of the acyl chains leads to dynamic encounters with the solvated outer shell of the micelle, providing an explanation for long-standing differences in models of micelle hydration. Altogether, our results provide fundamental understanding of physical characteristics of micelles that can be utilized to study other types of detergents and proteomicelle complexes.

Objective: The objective of this study was to measure the effect of micromagnetic stimulation (μMS) on hippocampal neurons, by using single microcoil (μcoil) prototype, Magnetic Pen (MagPen). MagPen will be used to stimulate the CA3 magnetically and excitatory post synaptic potential (EPSP) measurements will be made from the CA1. The threshold for μMS as a function of stimulation frequency of the current driving the µcoil will be demonstrated. Finally, the optimal stimulation frequency of the current driving the μcoil to minimize power will be estimated. Approach: A biocompatible prototype, MagPen was built, and customized such that it is easy to adjust the orientation of the μcoil over the hippocampal tissue in an in vitro setting. Finite element modeling (FEM) of the μcoil was performed to estimate the spatial profiles of the magnetic flux density (in T) and the induced electric fields (in V/m). The induced electric field profiles generated at different values of current applied to the µcoil whether can elicit a neuron response was validated by numerical modeling. The modeling settings were replicated in experiments on rat hippocampal neurons. Main results: The preferred orientation of MagPen over the Schaffer Collateral fibers was demonstrated such that they elicit a neuron response. The recorded EPSPs from CA1 due to μMS at CA3 were validated by applying tetrodotoxin (TTX). Finally, it was interpreted through numerical analysis that increasing frequency of the current driving the μcoil, led to a decrease in the current amplitude threshold for μMS. Significance: This work reports that μMS can be used to evoke population EPSPs in the CA1 of hippocampus. It demonstrates the strength-frequency curve for µMS and its unique features related to orientation dependence of the µcoils, spatial selectivity and distance dependence. Finally, the challenges related to µMS experiments were studied including ways to overcome them.

No abstract

Experimental and theoretical studies are presented on the design of perturbations that enhance desynchronization in populations of oscillators that are synchronized by periodic entrainment. A phase reduction approach is used to determine optimal perturbation timing based upon experimentally measured phase response curves. The effectiveness of the perturbation waveforms is tested experimentally in populations of periodically and stochastically synchronized chemical oscillators. The relevance of the approach to therapeutic methods for disrupting phase coherence in groups of stochastically synchronized neuronal oscillators is discussed.

Assessing drug permeability across the blood-brain barrier (BBB) is important when evaluating the abuse potential of new pharmaceuticals as well as developing novel therapeutics that target central nervous system disorders. One of the gold-standard in vivo methods for determining BBB permeability is rodent log BB; however, like most in vivo methods, it is time-consuming and expensive. In the present study, two statistical-based quantitative structure-activity relationship (QSAR) models were developed to predict BBB permeability of drugs based on their chemical structure. The in vivo BBB permeability data were harvested for 921 compounds from publicly available literature, non-proprietary drug approval packages, and University of Washington’s Drug Interaction Database. The cross-validation performance statistics for the BBB models ranged from 82 to 85% in sensitivity and 80–83% in negative predictivity. Additionally, the performance of newly developed models was assessed using an external validation set comprised of 83 chemicals. Overall, performance of individual models ranged from 70 to 75% in sensitivity, 70–72% in negative predictivity, and 78–86% in coverage. The predictive performance was further improved to 93% in coverage by combining predictions across the two software programs. These new models can be rapidly deployed to predict blood brain barrier permeability of pharmaceutical candidates and reduce the use of experimental animals.

Proteorhodopsin (PR) is a microbial proton pump that is ubiquitous in marine environments and may play an important role in the oceanic carbon cycle. Photoisomerization of the retinal chromophore in PR leads to a series of proton transfers between specific acidic amino acid residues and the Schiff base of retinal, culminating in a proton motive force to facilitate ATP synthesis. The proton donor in a similar retinal protein, bacteriorhodopsin, acts as a latch to allow the influx of bulk water. However, it is unclear if the proton donor in PR, E108, utilizes the same latch mechanism to become internally hydrated. Here, we used molecular dynamics simulations to model the changes in internal hydration of the blue variant of PR during photoactivation with the proton donor in protonated and deprotonated states. We find that there is a stark contrast in the levels of internal hydration of the cytoplasmic half of PR based on the protonation state of E108. Instead of a latch mechanism, deprotonation of E108 acts as a gate, taking advantage of a nearby polar residue (S61) to promote the formation of a stable water wire from bulk cytoplasm to the retinal-binding pocket over hundreds of nanoseconds. No large-scale conformational changes occur in PR over the microsecond timescale. This subtle yet clear difference in the effect of deprotonation of the proton donor in PR may help explain why the photointermediates that involve the proton donor (i.e., M and N states) have timescales that are orders of magnitude different from the archaeal proton pump, bacteriorhodopsin. In general, our study highlights the importance of understanding how structural fluctuations lead to differences in the way that retinal proteins accomplish the same task.

Synchronous behavior of a population of chemical oscillators is analyzed in the presence of both weak and strong coupling. In each case, we derive upper bounds on the critical coupling strength which are valid for arbitrary populations of nonlinear, heterogeneous oscillators. For weak perturbations, infinitesimal phase response curves are used to characterize the response to coupling, and graph theoretical techniques are used to predict synchronization. In the strongly perturbed case, we observe a phase dependent perturbation threshold required to elicit an immediate spike and use this behavior for our analytical predictions. Resulting upper bounds on the critical coupling strength agree well with our experimental observations and numerical simulations. Furthermore, important system parameters which determine synchronization are different in the weak and strong coupling regimes. Our results point to new strategies by which limit cycle oscillators can be studied when the applied perturbations become strong enough to immediately reset the phase.

ObjectiveThe objective of this study was to measure the effect of micromagnetic stimulation (μMS) on hippocampal neurons, by using single microcoil (μcoil) prototype, Magnetic Pen (MagPen). MagPen will be used to stimulate the CA3 region magnetically and excitatory post synaptic potential (EPSP) response measurements will be made from the CA1 region. The threshold for micromagnetic neurostimulation as a function of stimulation frequency of the current driving the μcoil will be demonstrated. Finally, the optimal stimulation frequency of the current driving the μcoil to minimize power will be estimated.ApproachA biocompatible, watertight, non-corrosive prototype, MagPen was built, and customized such that it is easy to adjust the orientation of the μcoil and its distance over the hippocampal tissue in an in vitro recording setting. Finite element modeling (FEM) of the μcoil design was performed to estimate the spatial profiles of the magnetic flux density (in T) and the induced electric fields (in V/m). The induced electric field profiles generated at different values of current applied to the μcoil can elicit a neuron response, which was validated by numerical modeling. The modeling settings for the μcoil were replicated in experiments on rat hippocampal neurons.Main resultsThe preferred orientation of MagPen over the Schaffer Collateral fibers was demonstrated such that they elicit a neuron response. The recorded EPSPs from CA1 region due to μMS at CA3 region were validated by applying tetrodotoxin (TTX). Application of TTX to the hippocampal slice blocked the EPSPs from μMS while after prolonged TTX washout, a partial recovery of the EPSP from μMS was observed. Finally, it was interpreted through numerical analysis that increasing frequency of the current driving the μcoil, led to a decrease in the current amplitude threshold for micromagnetic neurostimulation.SignificanceThis work reports that micromagnetic neurostimulation can be used to evoke population EPSP responses in the CA1 region of the hippocampus. It demonstrates the strengthfrequency curve for μMS and its unique features related to orientation dependence of the μcoils, spatial selectivity and stimulation threshold related to distance dependence. Finally, the challenges related to μMS experiments were studied including ways to overcome them.