Modulation of quinpirole-induced compulsive-like behavior in rats by environmental changes: Implications for OCD rituals and for exploration and navigation

Background  

Rats treated chronically with the D_2–3 dopamine agonist quinpirole were previously proposed as an animal model of obsessive-compulsive disorder (OCD) since their behavior is based on repeated, compulsive-like persistent traveling between a few places in the open field. The aim of the present study was to determine properties of the physical environment that shape such behavior. For this, quinpirole-treated rats were first exposed to an arena with an array of objects (landmarks) and after the development of compulsive-like behavior, the arena was manipulated by multiplying the number of objects, changing their spacing, relocating object array, or removing the objects.     

Marine inventory routing: shipments planning

This paper addresses a shipments-planning problem faced by producers of large volume liquid bulk products. Producing origins with limited tank storage capacity supply multiple products by ships (or barges) to consuming destinations that also have limited storage capacity. Timing, origin, destination, and product quantities of shipments have to be determined in a manner that minimizes costs and does not violate storage capacity constraints at both ends (neither stopping production at the origins, nor running out of stock at the destinations). A mixed integer-programming model is used to derive cost effective solutions within a few minutes. A cost-based heuristic algorithm is used to assure that acceptable solutions are obtained quickly.     

Temperature dependence of dimerization and dewetting of large-scale hydrophobes: a molecular dynamics study

We studied by molecular dynamics simulations the temperature dependence of hydrophobic association and drying transition of large-scale solutes. Similar to the behavior of small solutes, we found the association process to be characterized by a large negative heat capacity change. The origin of this large change in heat capacity is the high fragility of hydrogen bonds between water molecules at the interface with hydrophobic solutes; an increase in temperature breaks more hydrogen bonds at the interface than in the bulk. With increasing temperature, both entropy and enthalpy changes for association strongly decrease, while the change in free energy weakly varies, exhibiting a small minimum at high temperatures. At around T=Ts=360 K, the change in entropy is zero, a behavior similar to the solvation of small nonpolar solutes. Unexpectedly, we find that at Ts, there is still a substantial orientational ordering of the interfacial water molecules relative to the bulk. Nevertheless, at this point, the change in entropy vanishes due to a compensating contribution of translational entropy. Thus, at Ts, there is rotational order and translational disorder of the interfacial water relative to bulk water. In addition, we studied the temperature dependence of the drying-wetting transition. By calculating the contact angle of water on the hydrophobic surface at different temperatures, we compared the critical distance observed in the simulations with the critical distance predicted by macroscopic theory. Although the deviations of the predicted from the observed values are very small (8-23%), there seems to be an increase in the deviations with an increase in temperature. We suggest that these deviations emerge due to increased fluctuations, characterizing finite systems, as the temperature increases.     

Diazonium-functionalized horseradish peroxidase immobilized via addressable electrodeposition: direct electron transfer and electrochemical detection

A simple one-step procedure is introduced for the preparation of diazonium-enzyme adducts. The direct electrically addressable deposition of diazonium-modified enzymes is examined for electrochemical sensor applications. The deposition of diazonium-horseradish peroxidase leads to the direct electron transfer between the enzyme and electrode exhibiting a heterogeneous rate constant, ks, of 10.3 +/- 0.7 s-1 and a DeltaEp of 8 mV (v = 150 mV/s). The large ks and low DeltaEp are attributed to the intimate contact between enzyme and electrode attached by one to three phenyl molecules. Such an electrode shows high nonmediated catalytic activity toward H2O2 reduction. Future generations of arrayed electrochemical sensors and studies of direct electron transfer of enzymes can benefit from protein electrodes prepared by this method.     

Effect of ions on the hydrophobic interaction between two plates

We use molecular dynamics simulations to investigate the solvent mediated attraction and drying between two nanoscale hydrophobic surfaces in aqueous salt solutions. We study these effects as a function of the ionic charge density, that is, the ionic charge per unit ionic volume, while keeping the ionic diameter fixed. The attraction is expressed by a negative change in the free energy as the plates are brought together, with enthalpy and entropy changes that both promote aggregation. We find a strong correlation between the strength of the hydrophobic interaction and the degree of preferential binding/exclusion of the ions relative to the surfaces. The results show that amplification of the hydrophobic interaction, a phenomenon analogous to salting-out, is a purely entropic effect and is induced by high-charge-density ions that exhibit preferential exclusion. In contrast, a reduction of the hydrophobic interaction, analogous to salting-in, is induced by low-charge-density ions that exhibit preferential binding, the effect being either entropic or enthalpic. Our findings are relevant to phenomena long studied in solution chemistry, as we demonstrate the significant, yet subtle, effects of electrolytes on hydrophobic aggregation and collapse.     

Reagentless electrochemical immunoassay using electrocatalytic nanoparticle-modified antibodies

We describe a new approach for reagentless electrochemical immunoassay sensing in which Au/Pd NPs can be "loaded" onto antibodies to create an electrocatalytic antibody that is sensitive to the oxygen reduction reaction.     

Light-activated antibacterial surfaces comprise photosensitizers

Antibacterial surfaces were prepared using a base polyethylene sheet topped with a layer containing a mixed powder of poly (vinylidene fluoride) and photosensitizers (PSs). A crimpled stamp was placed on the mixed powder, and then it was passed through a heating and pressing device. The three chosen PSs were rose bengal, toluidine blue O and methylene blue. Scanning electron microscope analysis showed that the PS surface texture was coarse and highly developed. Measurement of the apparent contact angles of the droplets deposited on the PS surfaces using goniometry showed that all three surfaces were hydrophobic. Photodynamic analysis of the surfaces into which the PSs were incorporated indicated significant reactive oxygen species formation after illumination with light fluency rate of 1.46 mW cm(-2) for 30 min. Photodynamic inactivation assays performed in nutrient broth demonstrated more than 4 log reduction of the attached Escherichia coli after illumination (1.46 mW cm(-2)) for 24 h when the inoculum was 10(3) CFU mL(-1). However, more than 4 log reduction of Staphylococcus aureus occurred even when the cultures were illuminated for only 6 h. Our results provide an inexpensive, simple, state-of-the-art method for preparing antibacterial surfaces that may help prevent infections in hospital surroundings and in some medical devices.     

Development of a novel class of B-Raf(V600E)-selective inhibitors through virtual screening and hierarchical hit optimization

Oncogenic mutations in critical nodes of cellular signaling pathways have been associated with tumorigenesis and progression. The B-Raf protein kinase, a key hub in the canonical MAPK signaling cascade, is mutated in a broad range of human cancers and especially in malignant melanoma. The most prevalent B-Raf(V600E) mutant exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy. Herein, we describe the development of novel B-Raf(V600E) selective inhibitors via multi-step virtual screening and hierarchical hit optimization. Nine hit compounds with low micromolar IC(50) values were identified as B-Raf(V600E) inhibitors through virtual screening. Subsequent scaffold-based analogue searching and medicinal chemistry efforts significantly improved both the inhibitor potency and oncogene selectivity. In particular, compounds and possess nanomolar IC(50) values with selectivity for B-Raf(V600E)in vitro and exclusive cytotoxicity against B-Raf(V600E) harboring cancer cells.     

Thin Shell Implies Spectral Gap Up to Polylog via a Stochastic Localization Scheme

We consider the isoperimetric inequality on the class of high-dimensional isotropic convex bodies. We establish quantitative connections between two well-known open problems related to this inequality, namely, the thin shell conjecture, and the conjecture by Kannan, Lovász, and Simonovits, showing that the corresponding optimal bounds are equivalent up to logarithmic factors. In particular we prove that, up to logarithmic factors, the minimal possible ratio between surface area and volume is attained on ellipsoids. We also show that a positive answer to the thin shell conjecture would imply an optimal dependence on the dimension in a certain formulation of the Brunn–Minkowski inequality. Our results rely on the construction of a stochastic localization scheme for log-concave measures.     

Compartment-specific q-space analysis of diffusion-weighted data from isolated rhesus optic and sciatic nerves

We investigated compartment-specific water diffusion properties in two widely structurally different isolated bovine nerves. Sciatic and optic nerves were immersed in saline containing Gd-DTPA(2+). Consequently, T(1) became non-monoexponential and fit well to a biexponential function. q-Space diffusion data were collected for each component. In the sciatic nerve, the slow-decaying component (T(1s)) was considerably more restricted and directional than the fast-decaying component (T(1f)). In the optic nerve, fractional anisotropy of both components was comparable and similar to that of the total H(2)O signal. The root mean square of the displacement distribution functions of T(1s) correlated well with the widely different axonal diameters of both nerves. Possibly, the source of T(1s) is the intra-axonal compartment and that of T(1f) is associated with the inter-axonal space. The compartment specificity of the method shown makes it useful for the investigation of the contribution of each nerve compartment to diffusion tensor imaging measurements and other diffusion-based methods.