Ana M. Rubio

Changes in interleukin-1 signal modulators induced by 3,4-methylenedioxymethamphetamine (MDMA): regulation by CB2 receptors and implications for neurotoxicity

Background3,4-Methylenedioxymethamphetamine (MDMA) produces a neuroinflammatory reaction in rat brain characterized by an increase in interleukin-1 beta (IL-1β) and microglial activation. The CB2 receptor agonist JWH-015 reduces both these changes and partially protects against MDMA-induced neurotoxicity. We have examined MDMA-induced changes in IL-1 receptor antagonist (IL-1ra) levels and IL-1 receptor type I (IL-1RI) expression and the effects of JWH-015. The cellular location of IL-1β and IL-1RI was also examined. MDMA-treated animals were given the soluble form of IL-1RI (sIL-1RI) and neurotoxic effects examined.MethodsDark Agouti rats received MDMA (12.5 mg/kg, i.p.) and levels of IL-1ra and expression of IL-1RI measured 1 h, 3 h or 6 h later. JWH-015 (2.4 mg/kg, i.p.) was injected 48 h, 24 h and 0.5 h before MDMA and IL-1ra and IL-1RI measured. For localization studies, animals were sacrificed 1 h or 3 h following MDMA and stained for IL-1β or IL-1RI in combination with neuronal and microglial markers. sIL-1RI (3 μg/animal; i.c.v.) was administered 5 min before MDMA and 3 h later. 5-HT transporter density was determined 7 days after MDMA injection.ResultsMDMA produced an increase in IL-ra levels and a decrease in IL-1RI expression in hypothalamus which was prevented by CB2 receptor activation. IL-1RI expression was localized on neuronal cell bodies while IL-1β expression was observed in microglial cells following MDMA. sIL-1RI potentiated MDMA-induced neurotoxicity. MDMA also increased IgG immunostaining indicating that blood brain-barrier permeability was compromised.ConclusionsIn summary, MDMA produces changes in IL-1 signal modulators which are modified by CB2 receptor activation. These results indicate that IL-1β may play a partial role in MDMA-induced neurotoxicity.

Monte Carlo calculations for the intrinsic viscosity of several dendrimer molecules

We have performed Monte Carlo simulations to reproduce the intrinsic viscosity corresponding to different generation of several types of dendrite molecules: polyamidoamine dendrimers with an ethylendiamine core, polypropylene-imine with a diaminobutane core, and monodendrons and tridendrons of polybenzylether. With this end, we have employed coarse-grained idealizations of the molecules constituted by only two beads in each repeat unit (one in a branching or end unit and one intermediate along the repeat unit) and a simple hard-sphere potential between non-neighboring beads. Our goal is to investigate if this simple model is able to provide a reasonable description of some differences between these systems that have been observed experimentally, in particular, the location of the maximum in the intrinsic viscosity as a function of the generation number. Experimental radii of gyration in a given solvent are reproduced by a fit of the hard-sphere potential diameter. Subsequently, intrinsic viscosities are calculated by the variational approach of Fixman, which yields an accurate lower-bound value with an additional hydrodynamic interaction parameter (the friction radius of the beads). The results show a pronounced variation of the maximum location with the value of the friction radius and the structural details that cannot be mimicked with simpler models. The initial conformations for the Monte Carlo procedure are taken from atomistic configurations thermalized by means of a molecular dynamics.

Characterization of the theta state and transition curves of off‐lattice three dimensional chains

We have performed a Monte Carlo study of the dimensions (radius of gyration) and the intrinsic viscosity for three dimensional linear chains of different lengths. The chains are composed of Gaussian units which interact through a 6–12 Lennard‐Jones potential. From the study of the radius of gyration, the theta state has been characterized for this model. Moreover, the results for different temperatures and chain lengths have been plotted in terms of transition curves in order to analyze the collapse and excluded volume limiting behaviors. Also, a lower bound for the viscosity parameter Φ has been obtained in the theta state, as well as in the collapse and excluded volume regimes.

Dynamics of bond-fluctuation model chains in good and theta solvents

The dynamic Monte Carlo algorithm is employed to explore the dynamics of flexible linear chains. The chains are represented by the bond-fluctuation model with and without attractions between non-bonded units placed at close distances. This mimics the behavior of real chains in the good and poorer solvents. We obtain the chain sizes, diffusion coefficients, Rouse modes, and their relaxation times, We also evaluate the time correlation function of the end-to-end vector at different concentrations. Subsequently, we compare the dependence of the simulation results on chain length, solvent quality, concontration. and mode order with the correspunding theoretical predications. We observe a retardation of diffusion for non-dilute systems close to the theta state. This retardation is too high to be exclusively attributed to the increase of global friction and can be caused by temporary adherence of the chains to transient clusters.

Gibbs ensemble simulation of symmetric mixtures composed by the homopolymers AA, BB and their common block copolymer AB

A Gibbs ensemble algorithm implemented previously for mixtures of homopolymers and copolymers in a cubic lattice with coordination number z=26 is now used to characterize the complete phase separation diagram of the ternary mixtures formed by AA and BB homopolymers and their common symmetric diblock copolymer AB, all chains of the same length. We consider two alternative types of systems with repulsions between neighboring A and B units or with attractions between A and A or B and B neighboring units. A certain proportion of voids is included in both cases. The 3-phase region of the diagram is obtained by using a 3-box algorithm that has not been previously employed for polymer mixtures. The 3-phase region is composed of two homopolymer-rich asymmetric phases, each one mainly composed of a different homopolymer component together with a small proportion of copolymer. These two phases are in equilibrium with a third phase rich in copolymer. The 3-phase region connects smoothly with the 2-phase region cover...

Evolutionary method for the assembly of rigid protein fragments

Genetic algorithms constitute a powerful optimization method that has already been used in the study of the protein folding problem. However, they often suffer from a lack of convergence in a reasonably short time for complex fitness functions. Here, we propose an evolutionary strategy that can reproducibly find structures close to the minimum of a potential function for a simplified protein model in an efficient way. The model reduces the number of degrees of freedom of the system by treating the protein structure as composed of rigid fragments. The search incorporates a double encoding procedure and a merging operation from subpopulations that evolve independently of one another, both contributing to the good performance of the full algorithm. We have tested it with protein structures of different degrees of complexity, and present our conclusions related to its possible application as an efficient tool for the analysis of folding potentials.

Phase separation of binary homopolymer and ternary homopolymer–copolymer mixtures through Gibbs ensemble simulations

A Gibbs ensemble algorithm is implemented for mixtures of homopolymers and copolymers in a cubic lattice with coordination number z=26. We consider symmetric binary mixtures of homopolymer chains and also study the influence of the presence of symmetric diblock copolymers on these mixtures. All the chain lengths in a given mixture are identical (chains up to 128 units are included). A certain proportion of vacancies is introduced in each simulation. The phase separation curves are characterized by fitting the coexistence data to theoretical expressions. The dependence of the critical temperature on chain length, fraction of vacancies and also on the volume fraction of the copolymer in the mixture has been analyzed. Despite differences between models, the conclusions with this algorithm are similar to those obtained from previous simulations performed with techniques in which finite size interfacial effects may be important. Since the computational cost of our algorithm is reasonable, the present method ca...

THETA STATE AND COLLAPSE OF OFF-LATTICE CHAINS IN TWO DIMENSIONS

We have performed a Monte Carlo study of dimensions for two dimensional linear chains of different lengths. These chains are composed of Gaussian units which interact through a 6‐12 Lennard‐Jones potential. From this study, the theta state for this model has been characterized. Scaling curves have been obtained and different universal exponents, such as the theta point exponent ν, νθ, and the cross‐over exponent Φt have been numerically evaluated. The results are compared with theoretical predictions and with the values corresponding to simulations in lattice models. The results for ν and νθ agree with the theory, but our best estimation for the cross‐over exponent is closer to the simple mean field estimation.

Tricritical behavior of an off-lattice flexible polymer model: Monte Carlo calculation of second virial coefficients

Simulation data of second virial coefficients have been obtained for an off-lattice model of linear polymer chains by means of Monte Carlo method with different values of the variable that describes intramolecular attractions between units. The data have allowed us to study the theta, or tricritical, region where binary interactions cancel out. These Monte Carlo results are quantitatively compared with numerical predictions from the tricritical renormalization group theory. With this purpose, we have employed the same values for the three-body and the cutoff theoretical parameters that were previously used to reproduce the mean size data.

Influence of the hydrophobic face width on the degree of association of coiled-coil proteins

A very simplistic computational model for the simulation of the association of dimeric coiled–coil proteins has been extended to permit the formation of higher order quaternary structures. The main parameter of the new model is ω, the width of the potential well representing the attraction among hydrophobic residues. For values of ω ranging from 0.5 to 3.0 A, our Monte Carlo simulations predict the formation of trimers at low temperatures. The different structures (monomers, dimers, and trimers) which populate the simulated system at various temperatures allow us to discuss the optimum value of ω from the point of view of the thermal unfolding transition. On the other hand, the detailed analysis of the trimer structure provides a different point of view about the performance of the model, when compared with the structural information experimentally available for trimeric coiled–coils.