Role of Solvation on Diffusion of Ions in Diblock Copolymers: Understanding the Molecular Weight Effect through Modeling.

Salt-doped diblock copolymers with microphase-separated domains of both an ion conductive and a mechanically strong polymer have been extensively studied due to their potential in transport applications. Several unusual or counterintuitive trends regarding their transport properties have been observed experimentally, such as increasing ion conduction as a function of molecular weight. A crucial feature of these systems is the strong solvation of ions in the conducting microphase due to its higher dielectric constant. Here, we perform molecular dynamics simulations using a coarse-grained model that includes a 1/r4 potential form to generically represent ion solvation, allowing us to reproduce experimentally observed trends and explore their molecular underpinnings. We find that increasing ion concentration can increase or decrease ion diffusion, depending on solvation strength. We also show that the trend of increasing diffusion with molecular weight becomes more dramatic as ions are solvated in one polymer block more strongly or as the ion-ion interactions get stronger. In contrast to expectations, the interfacial width or the overlap of ions with the nonconductive polymer block does not adequately explain this phenomenon; instead, local ion agglomeration best explains reduced diffusion. Interfacial sharpening, controlled by the Flory χ parameter and molecular weight, tends to allow ions to spread more uniformly, and this increases their diffusion.

In Silico Modeling of Biofilm Formation by Nontypeable Haemophilus influenzae In Vivo.

Biofilms formed by nontypeable Haemophilus influenzae (NTHI) bacteria play an important role in multiple respiratory tract diseases. Visual inspection of the morphology of biofilms formed during chronic infections shows distinct differences from biofilms formed in vitro To better understand these differences, we analyzed images of NTHI biofilms formed in the middle ears of Chinchilla lanigera and developed an in silico agent-based model of the formation of NTHI biofilms in vivo We found that, as in vitro, NTHI bacteria are organized in self-similar patterns; however, the sizes of NTHI clusters in vivo are more than 10-fold smaller than their in vitro counterparts. The agent-based model reproduced these patterns and suggested that smaller clusters occur due to elimination of planktonic NTHI cells by the host responses. Estimation of model parameters by fitting simulation results to imaging data showed that the effects of several processes in the model change during the course of the infection.IMPORTANCE Multiple respiratory illnesses are associated with formation of biofilms within the human airway by NTHI. However, a substantial amount of our understanding of the mechanisms that underlie NTHI biofilm formation is obtained from in vitro studies. Our in silico model that describes biofilm formation by NTHI within the middle ears of Chinchilla lanigera will help isolate processes potentially responsible for the differences between the morphologies of biofilms formed in vivo versus those formed in vitro Thus, the in silico model can be used to glean mechanisms that underlie biofilm formation in vivo and connect those mechanisms to those obtained from in vitro experiments. The in silico model developed here can be extended to investigate potential roles of specific host responses (e.g., mucociliary clearance) on NTHI biofilm formation in vivo The developed computational tools can also be used to analyze and describe biofilm formation by other bacterial species in vivo.

Ion Correlation Effects in Salt-Doped Block Copolymers.

We apply classical density functional theory to study how salt changes the microphase morphology of diblock copolymers. Polymers are freely jointed and one monomer type favorably interacts with ions, to account for the selective solvation that arises from different dielectric constants of the microphases. By including correlations from liquid state theory of an unbound reference fluid, the theory can treat chain behavior, microphase separation, ion correlations, and preferential solvation, at the same coarse-grained level. We show good agreement with molecular dynamics simulations.

Diffusion in Lamellae, Cylinders, and Double Gyroid Block Copolymer Nanostructures.

We study transport of penetrants through nanoscale morphologies motivated by common block copolymer morphologies, using confined random walks and coarse-grained simulations. Diffusion through randomly oriented grains is 1/3 for cylinder and 2/3 for lamellar morphologies versus an unconstrained (homopolymer) system, as previously understood. Diffusion in the double gyroid structure depends on the volume fraction and is 0.47-0.55 through the minority phase at 30-50 vol % and 0.73-0.80 through the majority at 50-70 vol %. Thus, among randomly oriented standard minority phase structures with no grain boundary effects, lamellae is preferable for transport.

Advanced Airway Type and Its Association with Chest Compression Interruptions During Out-of-Hospital Cardiac Arrest Resuscitation Attempts.

OBJECTIVE: To assess interruptions in chest compressions associated with advanced airway placement during cardiopulmonary resuscitation (CPR) of out-of-hospital cardiac arrest (OHCA) victims. METHODS: The method used was observational analysis of prospectively collected clinical and defibrillator data from 339 adult OHCA victims, excluding victims with <5 minutes of CPR. Interruptions in CPR, summarized by chest compression fraction (CCF), longest pause, and the number of pauses greater than 10 seconds, were compared between patients receiving bag valve mask (BVM), supraglottic airway (SGA), endotracheal intubation (ETI) via direct laryngoscopy (DL), and ETI via video laryngoscopy (VL). Secondary outcomes included first pass success and the effect of multiple airway attempts on CPR interruptions. RESULTS: During the study period, paramedics managed 23 cases with BVM, 43 cases with SGA, 148 with DL, and 125 with VL. There were no statistically significant differences between the airway groups with regard to longest compression pause (BVM 18 sec [IQR 11-33], SGA 29 sec [IQR 15-65], DL 26 sec [IQR 12-59], VL 22 sec [IQR 14-41]), median number of pauses greater than 10 seconds (BVM 2 [IQR 1-3], SGA 2 [IQR 1-3], DL 2 [IQR 1-4], VL 2 [IQR 1-3]), or CCF (0.92 for all groups). However, each additional attempt following failed initial DL was associated with an increase in the risk of additional chest compression pauses (relative risk 1.29, 95% confidence interval 1.02-1.64). Such an association was not observed with additional attempts using VL or SGA. First pass success was highest with SGA (77%), followed by between DL (68%) and VL (67%); these differences were not statistically significant. CONCLUSIONS: While summary measures of chest compression delivery did not differ significantly between airway classes in this observational study, repeated attempts following failed initial DL during cardiopulmonary resuscitation were associated with an increase in the number of pauses in chest compression delivery observed.

Diffusion of Selective Penetrants in Interfacially Modified Block Copolymers from Molecular Dynamics Simulations.

To show the influence of the interface on structure and dynamics of microphase separated polymer systems, we study interfacially modified AB block copolymers with small molecule penetrants. The polymers have a random midblock or tapered midblock whose composition varies from pure A to pure B (or from pure B to pure A for an inverse taper) between two pure blocks of A and B. We perform simple coarse-grained molecular dynamics simulations of symmetric polymers that form lamellae. With normal tapering, both polymer and penetrant diffusion parallel to the lamellae increases as taper length increases. Inverse tapered polymers exist in different conformational states (e.g., stretched vs folded back and forth across the interface) with different dynamic behavior, leading to nonmonotonic trends in their diffusion. However, the local mixing of monomers (rather than polymer conformation) appears to be the most important factor in determining penetrant diffusion.

Effect of sequence dispersity on morphology of tapered diblock copolymers from molecular dynamics simulations.

Tapered diblock copolymers are similar to typical AB diblock copolymers but have an added transition region between the two blocks which changes gradually in composition from pure A to pure B. This tapered region can be varied from 0% (true diblock) to 100% (gradient copolymer) of the polymer length, and this allows some control over the microphase separated domain spacing and other material properties. We perform molecular dynamics simulations of linearly tapered block copolymers with tapers of various lengths, initialized from fluids density functional theory predictions. To investigate the effect of sequence dispersity, we compare systems composed of identical polymers, whose taper has a fixed sequence that most closely approximates a linear gradient, with sequentially disperse polymers, whose sequences are created statistically to yield the appropriate ensemble average linear gradient. Especially at high segregation strength, we find clear differences in polymer conformations and microstructures between these systems. Importantly, the statistical polymers are able to find more favorable conformations given their sequence, for instance, a statistical polymer with a larger fraction of A than the median will tend towards the A lamellae. The conformations of the statistically different polymers can thus be less stretched, and these systems have higher overall density. Consequently, the lamellae formed by statistical polymers have smaller domain spacing with sharper interfaces.

Encapsulation of Nanoparticles During Polymer Micelle Formation: A Dissipative Particle Dynamics Study.

The formation of block copolymer micelles with and without hydrophobic nanoparticles is simulated using dissipative particle dynamics. We use the model developed by Spaeth et al. [ Spaeth , J. R. , Kevrekidis , I. G. , and Panagiotopoulos , A. Z. J. Chem. Phys. 2011 , 134 ( (16) ) 164902 ], and drive micelle formation by adjusting the interaction parameters linearly over time to represent a rapid change from organic solvent to water. For different concentrations of added nanoparticles, we determine characteristic times for micelle formation and coagulation, and characterize micelles with respect to size, polydispersity, and nanoparticle loading. Four block copolymers with different numbers of hydrophobic and hydrophilic polymer beads, are examined. We find that increasing the number of hydrophobic beads on the polymer decreases the micelle formation time and lowers polydispersity in the final micelle distribution. Adding more nanoparticles to the simulation has a negligible effect on micelle formation and coagulation times, and monotonically increases the polydispersity of the micelles for a given polymer system. The presence of relatively stable free polymer in one system decreases the amount of polymer encapsulating the nanoparticles, and results in an increase in polydispersity and the number of nanoparticles per micelle for that system, especially at high nanoparticle concentration. Longer polymers lead to micelles with a more uniform nanoparticle loading.

Fluids density functional theory and initializing molecular dynamics simulations of block copolymers.

Classical, fluids density functional theory (fDFT), which can predict the equilibrium density profiles of polymeric systems, and coarse-grained molecular dynamics (MD) simulations, which are often used to show both structure and dynamics of soft materials, can be implemented using very similar bead-based polymer models. We aim to use fDFT and MD in tandem to examine the same system from these two points of view and take advantage of the different features of each methodology. Additionally, the density profiles resulting from fDFT calculations can be used to initialize the MD simulations in a close to equilibrated structure, speeding up the simulations. Here, we show how this method can be applied to study microphase separated states of both typical diblock and tapered diblock copolymers in which there is a region with a gradient in composition placed between the pure blocks. Both methods, applied at constant pressure, predict a decrease in total density as segregation strength or the length of the tapered region is increased. The predictions for the density profiles from fDFT and MD are similar across materials with a wide range of interfacial widths.

Adenosine 5'-monophosphate-activated protein kinase regulates IL-10-mediated anti-inflammatory signaling pathways in macrophages.

AMP-activated protein kinase (AMPK) is a conserved serine/threonine kinase with a critical function in the regulation of metabolic pathways in eukaryotic cells. Recently, AMPK has been shown to play an additional role as a regulator of inflammatory activity in leukocytes. Treatment of macrophages with chemical AMPK activators, or forced expression of a constitutively active form of AMPK, results in polarization to an anti-inflammatory phenotype. In addition, we reported previously that stimulation of macrophages with anti-inflammatory cytokines such as IL-10, IL-4, and TGF-ß results in rapid activation of AMPK, suggesting that AMPK contributes to the suppressive function of these cytokines. In this study, we investigated the role of AMPK in IL-10-induced gene expression and anti-inflammatory function. IL-10-stimulated wild-type macrophages displayed rapid activation of PI3K and its downstream targets Akt and mammalian target of rapamycin complex (mTORC1), an effect that was not seen in macrophages generated from AMPKα1-deficient mice. AMPK activation was not impacted by treatment with either the PI3K inhibitor LY294002 or the JAK inhibitor CP-690550, suggesting that IL-10-mediated activation of AMPK is independent of PI3K and JAK activity. IL-10 induced phosphorylation of both Tyr(705) and Ser(727) residues of STAT3 in an AMPKα1-dependent manner, and these phosphorylation events were blocked by inhibition of Ca(2+)/calmodulin-dependent protein kinase kinase ß, an upstream activator of AMPK, and by the mTORC1 inhibitor rapamycin, respectively. The impaired STAT3 phosphorylation in response to IL-10 observed in AMPKα1-deficient macrophages was accompanied by reduced suppressor of cytokine signaling 3 expression and an inadequacy of IL-10 to suppress LPS-induced proinflammatory cytokine production. Overall, our data demonstrate that AMPKα1 is required for IL-10 activation of the PI3K/Akt/mTORC1 and STAT3-mediated anti-inflammatory pathways regulating macrophage functional polarization.

Simulation of a small molecule analogue of a lithium ionomer in an external electric field.

We have investigated the ion dynamics in lithium-neutralized 2-pentylheptanoic acid, a small molecule analogue of a precise poly(ethylene-co-acrylic acid) lithium ionomer. Atomistic molecular dynamics simulations were performed in an external electric field. The electric field causes alignment of the ionic aggregates along the field direction. The energetic response of the system to an imposed oscillating electric field for a wide range of frequencies was tracked by monitoring the coulombic contribution to the energy. The susceptibility found in this manner is a component of the dielectric susceptibility typically measured experimentally. A dynamic transition is found and the frequency associated with this transition varies with temperature in an Arrhenius manner. The transition is observed to be associated with rearrangements of the ionic aggregates.

Phase Behavior of Tapered Diblock Copolymers from Self-Consistent Field Theory.

Tapered diblock copolymers are similar to AB diblock copolymers, but the sharp junction between the A and B blocks is replaced with a gradient region in which composition varies from mostly A to mostly B along its length. The A side of the taper can be attached to the A block (normal) or the B block (inverse). We demonstrate how taper length and direction affect the phase diagrams and density profiles using self-consistent field theory. Adding tapers shifts the order-disorder transition to lower temperature versus the diblock, and this effect is larger for longer tapers and for inverse tapers. However, tapered systems' phase diagrams and interfacial profiles do not simply match those of diblocks at a shifted effective temperature. For instance, we find that normal tapering widens the bicontinuous gyroid region of the phase diagram, while inverse tapering narrows this region, apparently due to differences in polymer organization at the interfaces.

Nonlinear dynamic heat capacity of a bead-spring polymeric glass former.

Nonlinear dynamics of a simple bead-spring glass-forming polymer were studied with molecular dynamics simulations. The energy response to sinusoidal variations in the temperature was tracked in order to evaluate the dynamic heat capacity. The amplitude dependence of the response is the focus of the current paper where pronounced nonlinear behavior is observed for large amplitudes in the temperature "driving force." We generalize the usual linear response analysis to the nonlinear regime so that higher order terms in the Fourier series of the energy response can be compactly analyzed. This is done by grouping all Fourier terms contributing to entropy generation into a "loss" contribution and the remainder yields the "storage" term. Finally, the bead-spring system is mapped onto three simpler models. First is a potential energy inspired "trap" model consisting of interconnected potential energy meta-basins and barriers. Second is the Tool-Narayanaswamy-Moynihan (TNM) model. Third is a version of the TNM model with a temperature dependent heat capacity. Qualitatively similar nonlinear behaviors are observed in all cases.

The potential energy landscape contribution to the dynamic heat capacity.

The dynamic heat capacity of a simple polymeric, model glassformer was computed using molecular dynamics simulations by sinusoidally driving the temperature and recording the resultant energy. The underlying potential energy landscape of the system was probed by taking a time series of particle positions and quenching them. The resulting dynamic heat capacity demonstrates that the long time relaxation is the direct result of dynamics resulting from the potential energy landscape. Moreover, the equilibrium (low frequency) portion of the potential energy landscape contribution to the heat capacity is found to increase rapidly at low temperatures and at high packing fractions. This increase in the heat capacity is explained by a statistical mechanical model based on the distribution of minima in the potential energy landscape.

Theory and simulation of the dynamic heat capacity of the east Ising model.

A recently developed methodology for the calculation of the dynamic heat capacity from simulation is applied to the east Ising model. Results show stretched exponential relaxation with the stretching exponent, beta, decreasing with decreasing temperature. For low temperatures, the logarithm of the relaxation time is approximately proportional to the inverse of the temperature squared, which is the theoretical limiting behavior predicted by theories of facilitated dynamics. In addition, an analytical approach is employed where the overall relaxation is a composite of relaxation processes of subdomains, each with their own characteristic time. Using a Markov chain method, these times are computed both numerically and in closed form. The Markov chain results are seen to match the simulations at low temperatures and high frequencies. The dynamics of the east model are tracked very well by this analytic procedure, and it is possible to associate features of the spectrum of the dynamic heat capacity with specific domain relaxation events.