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In this paper, the theoretical framework is a depth-integrated two-phase model capable of considering many essential physical aspects such as reproducing the propagation of debris flows with soil permeability ranging from high to low and considering the pore-water pressure evolution. In this model, the pore fluid is described by an additional set of depth-integrated balance equations in order to take into account the velocity of pore fluid. The model employs a frictional rheological law for the granular material, and the interstitial fluid is treated as a Newtonian fluid. A drag law describes the interaction between interstitial fluid and grains. The variables of permeability, porosity, and drag force are included in the governing equations to consider the interaction between the phases. This paper aims to extend a generalized two-phase depth-integrated model to enhance the description of the interaction between the two phases and their respective movements. It allows us to increase our understanding of the mechanism behind natural rapid landslides. To evaluate the developed approach, a set of dam-break problems has been performed. These simulations provide interesting information in simple and controlled situations on the landslide propagations with different degrees of soil permeability and the interaction between solid and fluid phases. The extended model has also been applied to simulate the dynamics of the Acheron rock avalanche, which is an appropriate benchmark to examine the applicability of the model to real cases. [ABSTRACT FROM AUTHOR]

The combination of natural resources with biologically active biocompatible ionic liquids (Bio-IL) is presented as a combinatorial approach for developing tools to manage inflammatory diseases. Innovative biomedical solutions were constructed combining silk fibroin (SF) and Ch[G allate ], a Bio-IL with antioxidant and anti-inflammatory features, as freeze-dried 3D-based sponges. An evaluation of the effect of the Ch[Gallate] concentration (≤3% w/v) on the SF/Ch[Gallate] sponges was studied. Structural changes observed on the sponges revealed that the Ch[Gallate] presence positively affected the β-sheet formation while not influencing the silk native structure, which was suggested by the FTIR and solid-state NMR results, respectively. Also, it was possible to modulate their mechanical properties, antioxidant activity and stability/degradation in an aqueous environment, by changing the Ch[Gallate] concentration. The architectures showed high water uptake ability and a weight loss that follows the controlled Ch[Gallate] release rate studied for 7 days. Furthermore, the sponges supported human adipose stem cells growth and proliferation, up to 7 days. TNF-α, IL-6 (pro-inflammatory) and IL-10 (anti-inflammatory) release quantification from a human monocyte cell line revealed a decrease in the pro-inflammatory cytokines concentrations in samples containing Ch[G allate ]. These outcomes encourage the use of the developed architectures as tissue engineering solutions, potentially targeting inflammation processes. Combining natural resources with active biocompatible ionic liquids (Bio-IL) is herein presented as a combinatorial approach for the development of tools to manage inflammatory diseases. We propose using silk fibroin (SF), a natural protein, with cholinium gallate, a Bio-IL, with antioxidant and anti-inflammatory properties, to construct 3D-porous sponges through a sustainable methodology. The morphological features, swelling, and stability of the architectures were controlled by Bio-IL content in the matrices. The sponges were able to support human adipose stem cells growth and proliferation, and their therapeutic effect was proved by the blockage of TNF-α from activated and differentiated THP-1 monocytes. We believe that these bio-friendly and bioactive SF/Bio-IL-based sponges are effective for targeting pathologies with associated inflammatory processes. [Display omitted] [ABSTRACT FROM AUTHOR]

Water content is one important factor on which velocities, heights, and runout of debris flows and similar phenomena depend. To this purpose, we need two ingredients (i) a mathematical model describing the incorporation of water into the moving soil, which results in a change of water content, and (ii) a rheological model with properties depending on the water content. Modeling of such problems can be done either by using either a: (i) two phases approach, where velocities of solid and water may be different, using two sets of nodes, or (ii) two phases approach where velocities of both are assumed to be the same, using a single set of nodes. In both cases, the models have to implement a mechanism for the water inflow -or outflow-. We will modify both types of two phases models (one or two sets of nodes for solid and water) to include the change of water content due to water inflow. Implementation in the SPH requires extending the algorithm and updating the smoothing length because it is based on the mass of particles and their relative position. Updating the smoothing length when only changes mass is to be avoided. Regarding the rheological model, we will introduce a new model for frictional debris flows implementing a Voellmy coefficient which depends on water content. Alternatively, we will propose a more consistent model based on Bagnold's idea of introducing a 1D concentration parameter (λ). Finally, we will illustrate the proposed model capability with two examples, a dam break problem, and a real case in El Salvador where the water content played an important role in the propagation properties of a debris flow. [ABSTRACT FROM AUTHOR]

Debris flows can be considered a type of landslide with large velocities and long run-out distances. There are many types of debris flows, depending on the properties of the solid and fluid components of the mixture. The triggering and propagation of debris flows can be studied using a single 3D mathematical model. The computational cost can be very high because of their length, and depth-integrated models provide a good combination of accuracy and cost. Both types of models can be combined in the analysis, using 3D models for initiation and at singular points where more accuracy is wanted. As in a chain where the strength is never higher than that of the weaker link, we have to ensure that all the models are accurate enough in a joint model. This paper deals with a new depth-integrated model which can take into account the changes caused by dewatering in a debris flow. An important limitation of existing two-phase models allowing different velocities of solid and water particles is that when water abandons the mixture, porosity decreases and tends to zero. Here, a two-layer model is introduced, including an unsaturated upper layer on top of a saturated layer. [ABSTRACT FROM AUTHOR]

Innovative approaches in nanotechnology can provide drug delivery systems with a high potential in different fields. To avoid trial and error assays as a main driving force governing new designs and, furthermore, to develop successful nanosystem optimization strategies, it is of the greatest importance to develop specific characterisation techniques beyond conventional determinations of size, zeta potential and morphology. However, the application of techniques able to determine some key characteristics, such as nanostructure (i.e., solid structure vs vesicular), and the way in which the reorganization of components takes place on these structures has been scarcely explored. The present work has been devoted to provide some insights about the potential offered by some NMR techniques to those scientists working on nanotechnological approaches. For this purpose, we selected our nanosystems based on sorbitan monooleate as a case study. We used 1 H NMR methods, including a recently proposed method relying in the well-known Saturation Transfer Difference (STD) experiment for the observation of ‘invisible signals’ in large aggregates (Invisible State STD or ISSTD). Overall, these techniques revealed the presence in these nanosystems of a gradient of flexibility from an internal rigid core towards a more flexible region located on their surface, as well as the absence of water content in both regions. Such structure, corresponding to a solid nanostructure rather than a vesicular one, can explain some of the interesting properties previously observed for these innovative nanosystems, such as their high stability, and allows us to refer to these nanosystems with the term “Solid Sorbitan esters Nanoparticles” (SSN). On the basis of the valuable information provided by the mentioned characterisation techniques, it is our understanding that they could facilitate the future design of new drug delivery nanosystems as well as the improvement of existing ones and/or the development of new applications for classical drug delivery concepts. [ABSTRACT FROM AUTHOR]

Background Emerging evidence suggests that near-roadway air pollution (NRP) exposure causes childhood asthma. The associated costs are not well documented. Objective We estimated the cost of childhood asthma attributable to residential NRP exposure and regional ozone (O 3 ) and nitrogen dioxide (NO 2 ) levels in Los Angeles County. We developed a novel approach to apportion the costs between these exposures under different pollution scenarios. Methods We integrated results from a study of willingness to pay to reduce the burden of asthma with results from studies of health care use and charges to estimate the costs of an asthma case and exacerbation. We applied those costs to the number of asthma cases and exacerbations caused by regional pollution in 2007 and to hypothetical scenarios of a 20% reduction in regional pollution in combination with a 20% reduction or increase in the proportion of the total population living within 75 m of a major roadway. Results Cost of air pollution–related asthma in Los Angeles County in 2007 was $441 million for O 3 and $202 million for NO 2 in 2010 dollars. Cost of routine care (care in absence of exacerbation) accounted for 18% of the combined NRP and O 3 cost and 39% of the combined NRP and NO 2 cost; these costs were not recognized in previous analyses. NRP-attributable asthma accounted for 43% (O 3 ) to 51% (NO 2 ) of the total annual cost of exacerbations and routine care associated with pollution. Hypothetical scenarios showed that costs from increased NRP exposure might offset savings from reduced regional pollution. Conclusions Our model disaggregates the costs of regional pollution and NRP exposure and illustrates how they might vary under alternative exposure scenarios. The cost of air pollution is a substantial burden on families and an economic loss for society. [ABSTRACT FROM AUTHOR]

Abstract: The study of the interaction of ghrelin (1), the endogenous ligand for the GH secretagogues receptor (GHS-R1a), and des-acyl ghrelin (2) with the GHS-R1a by NMR using living cells is presented, using GHS-R1a stably transfected cell lines (CHO and HEK 293) and wild type cells. Therefore, the interaction of 1 and 2 with the GHS-R1a receptor has been performed using quasi-physiological conditions. Ghrelin (1), showed a higher number of residues affected by chemical shift perturbation (CSP) or chemical shift exchange (CSE) effects: Ser3, Phe4, Leu5, Val12, Gln13/Gln14, Lys16/Lys19, Glu17 and Lys24 were much more affected in 1 than in des-acyl ghrelin (2). The chemical shift index CSI values indicated the presence of a possible α-helical region between Glu8 and Lys20 for ghrelin (1). After analysing the NMR data, two possible structures have arisen, which present different proline rotamers: the EEZE and the EZEZ conformers, at positions Pro7, Pro21, Pro22 and Pro27, respectively, keeping a left-handed α-helix from Glu8 to Lys20. These experimental evidences might imply that the GHS-R1a receptor is acting as a prolyl-cis/trans isomerase. [Copyright &y& Elsevier]

A debris flow is one of the most dangerous types of geophysical mass flows moving downward mountain slopes and consist of a mixture of soil and rocks with a significant quantity of interstitial fluid. They can travel at extremely rapid velocities affecting long distances due to the significant influence of pore-water pressures on the propagation stage. In this paper, a novel two-phase depth-integrated SPH numerical model is applied to simulate a debris flow in which the effects of bed entrainment and pore-water pressure evolution, essential components to performed debris flows risk assessment, are included. The model was applied to simulate the dynamics of Yu Tung debris flow which is an appropriate benchmark case to examine the applicability of the developed model, as bed entrainment and pore-water pressure evolution were key aspects that affected the moving mass dynamics. The developed two-phase depth-integrated SPH-FD model is applied to assess the structural countermeasure of the bottom drainage screen, used to reduce the impact of debris flows. The reasonable results obtained from the analysis indicate that the model is capable to properly reproduce the propagation of the debris flow and more importantly to correctly perform the time-space evolution of pore water pressures during the whole deformation process from initiation through propagation, over an impermeable and permeable bottom boundary, up to deposition. [ABSTRACT FROM AUTHOR]

• An exopolysaccharide (EPS) was isolated from bacterial mats in French Polynesia. • The structure repeating unit is →4)-b-D-GlcpA-(1→4)-a-D-GalpNAc-(1→3)-b-D-GlcpNAc-(1→4)-b-D-GlcpA-(1→. • MO245 has equal ratio of GlcA to N-acetylated sugars and the same glyosidic linkages than HA. • The structural similarity to HA provides MO245 with similar physicochemical properties. MO245 exopolysaccharide (EPS) was produced in laboratory conditions from Vibrio genus microorganism isolated from bacterial mats found in Moorea Island. Its structure consists of a linear tetrasaccharide repeating unit →4)-β-D-Glc p A-(1→4)-α-D-Gal p NAc-(1→3)-β-D-Glc p NAc-(1→4)-β-D-Glc p A-(1→ containing covalently-linked 5% of glucose, galactose, and rhamnose, determined by methylation analyses and NMR spectroscopy. The molecular weight, radius of gyration (R g) and intrinsic viscosity, [ η ], determined by gel permeation chromatography with light scattering and viscosity detection, were 513 ± 4 kDa (PDI, 1.42 ± 0.01), 6.7 ± 0.3 dl/g and 56 ± 0.3 nm respectively. The chelation of the EPS with copper divalent ions leads to the instantaneous formation of gels. The structural similitude proposed, based in an equal ratio of GlcA to N-acetylated sugars and in the same type of glyosidic linkages present in the repeating unit (alternated 1→3 and 1→4 linkages), is translated into analogous physicochemical properties: MO245 EPS is a flexible polyelectrolyte, with scaling exponents similar to that described for HA. This similitude opens opportunities in future drug delivery, tissue engineering, and cosmetic applications. [ABSTRACT FROM AUTHOR]

We explored the potential of two types of sorbitan ester nanoparticles (SENS) as novel tools for topical ocular drug delivery. The optimized SENS formulation (SENS-OPT) consisted of nanoparticles (NPs) of 170.5 nm, zeta potential +33.9 mV, and cyclosporine loading of 19.66%. After hyaluronic acid (HA) coating, the resulting SENS-OPT-HA NPs had a particle size of 177.6 nm and zeta potential of −20.6 mV. The NPs were stable during 3 months of storage at different temperatures and did not aggregate in the presence of protein-enriched simulated lacrimal fluid. There was no toxicity to cultured human corneal epithelial (HCE) cells when exposed to NPs up to 0.4% (w/v). Both NPs were effectively internalized by HCE cells through active mechanisms. Endocytosis of SENS-OPT NPs was caveolin-dependent whereas SENS-OPT-HA NP endocytosis was mediated by HA receptors. HA-receptor–mediated endocytosis may be responsible for the higher cellular uptake of SENS-OPT-HA NPs. After cyclosporine incorporation into the NPs, corneal penetration of this immunosuppressive drug by loaded SENS-OPT NPs was 1.3-fold higher than the commercial reference formulation Sandimmun®. For cyclosporine-loaded SENS-OPT-HA NPs, the penetration was 2.1-fold higher than for Sandimmun®. In ex vivo stimulated lymphocytes, both formulations demonstrated the same reduction in IL-2 levels as Sandimmun®. [ABSTRACT FROM AUTHOR]

Abstract: A comprehensive numerical model for the analysis of offshore foundations under a general transient loading is presented here. The theoretical basis of the model lies on the Swansea formulation of Biot’s equations of dynamic poroelasticity combined with a constitutive model that reproduces key aspects of cyclic soil behaviour in the frame of the theory of generalised plasticity. On the practical side, the adoption of appropriate finite element formulations may prevent the appearance of spurious numerical instabilities of the pore pressure field. In this respect, the use of a coupled enhanced-strain element is here proposed. On the other hand, the practicality of the presented model depends ultimately on its computational efficiency. Some practical recommendations concerning the solution strategies, the matrix storage/handling procedures and the parallel multi-processor computation are here provided. Finally, the performance of the model with a benchmark study case and its practical application to analyse the soil–structure interaction of an offshore monopile under a realistic transient storm loading are discussed. [Copyright &y& Elsevier]

Abstract: Rainfall-induced channelised landslides of the flow type may reach high velocities and travel large run-out distances. The proper modelling of the propagation stage is fundamental to risk analysis and management. The correct selection of mass rheology is fundamental to this procedure, and the variation of pore water pressures and bed entrainment along the landslide path must also be properly taken into account. All of these processes can be consistently simulated through a quasi-3D (depth-integrated) coupled SPH model. In this study, such a model is applied to a relevant case history from Southern Italy for which an advanced dataset is available. The numerical results provide a satisfactory back-analysis of the case history and clearly indicate that the bed entrainment rate and the extent of the erodible areas affect the propagation paths, the velocities and the deposition heights. On the basis of the results, general insights into this type of landslide are discussed with reference to different hypotheses for propagation modelling. [Copyright &y& Elsevier]

[Display omitted] Biodegradable poly(lactic-co-glycolic acid) microspheres (PLGA MSs) are attractive delivery systems for site-specific maintained release of therapeutic active substances into the intravitreal chamber. The design, development, and characterization of idebenone-loaded PLGA microspheres by means of an oil-in-water emulsion/solvent evaporation method enabled the obtention of appropriate production yield, encapsulation efficiency and loading values. MSs revealed spherical shape, with a size range of 10–25 μm and a smooth and non-porous surface. Fourier-transform infrared spectroscopy (FTIR) spectra demonstrated no chemical interactions between idebenone and polymers. Solid-state nuclear magnetic resonance (NMR), X-ray diffractometry, differential scanning calorimetry (DSC) and thermogravimetry (TGA) analyses indicated that microencapsulation led to drug amorphization. In vitro release profiles were fitted to a biexponential kinetic profile. Idebenone-loaded PLGA MSs showed no cytotoxic effects in an organotypic tissue model. Results suggest that PLGA MSs could be an alternative intraocular system for long-term idebenone administration, showing potential therapeutic advantages as a new therapeutic approach to the Leber's Hereditary Optic Neuropathy (LHON) treatment by intravitreal administration. [ABSTRACT FROM AUTHOR]

Highlights: [•] A new SPH model is presented for solving the 2D shallow water equations. [•] Well-balanced issue is thoroughly discussed in the context of SPH discretization. [•] Corrected SPH formulation is derived to ensure well-balanced solution. [•] The MUSCL approach is applied to enable Riemann solver based artificial viscosity. [•] Local bed modification method is proposed to prevent negative water depth. [ABSTRACT FROM AUTHOR]

Abstract: This work reports the synthesis of 2-hydroxy ethylammonium oleate and bis(2-hydroxy ethyl)ammonium oleate ionic liquids, which have a long aliphatic chain as well as the study of some of their physical properties, in particular the effect of temperature on their density, speed of sound, viscosity, and refractive index. 1H and 13C NMR spectra were used to characterize the chemical structure of the species in concordance with FT-IR spectra. DOSY NMR spectra were used to determine the self-diffusion coefficients of 2-hydroxy ethylammonium oleate ionic liquid, which were consistent with the formation of a lamellar or micellar liquid crystal phase; due the similar structure, a similar aggregation in the bis(2-hydroxy ethyl)ammonium oleate ionic liquid it is expected. [ABSTRACT FROM AUTHOR]

Landslide-generated wave (LGW) events are particularly dangerous as they are associated with a high risk of loss of life and severe economic damage. The lifecycle of a LGW can be decomposed into various distinct stages, such as generation and propagation. The modeling of the entire LGW lifecycle through the use of a single model is difficult as the hazard characteristics of LGWs differ widely across spatial and temporal scales. Therefore, this study proposed a Hybrid Smoothed Particle Hydrodynamics (SPH) - Boussinesq model to overcome the limitations of individual models and to acquire a more reliable method of analyzing LGWs. An SPH two-layer depth-integrated model was combined with a Boussinesq model (FUNWAVE) through the implementation of a transformation zone. The proposed hybrid model was then applied within the evaluation of the potential risk for the generation of LGWs by impulsive waves generated by the Halaowo Landslide in Jinsha River, China. This study provides a discussion of the process for predicting waves and generated a risk map according to the reference emergency response plan. • The process of landslide-generated waves is briefly decomposed into generation and propagation stages according to their physical characteristics. • A SPH two-layer depth-integrated model, providing a reasonable compromise between computational cost and accuracy, is applied to capture the generation stage of waves induced by landslide. • A Boussinesq model capable of solving many coastal processes such as: nearshore wave propagation & transformation, is practiced to investigate the wave propagation problems in river basin areas. • A transformation zone is implemented to deliver the physical features of impulsive waves from the near filed to the far field. • The proposed hybrid model is then applied to evaluate the potential tsunami risk of a river basin threaten by the probable failure of a nearshore slope. [ABSTRACT FROM AUTHOR]

Abstract This work presents the development of a bioelectrode based on catalase enzyme and a novel protic ionic liquid, pentaethylenehexammonium acetate (PEHAA), on a glassy carbon surface. PEHAA was synthesized for the first time and its structure was confirmed by FTIR and NMR. Viscosity and conductivity of PEHAA aqueous mixtures were measured and a Walden plot was used to analyze PEHAA ionicity. The bioelectrode was constructed using layer by layer (LBL) and electrochemical deposition (ECD) techniques. The catalase enzyme was immobilized on the surface of a glassy carbon electrode with the aid of the ionic liquid; the electrodes were evaluated by using cyclic voltammetry at various scan rates. The bioelectrode constructed in this work was stable; it lost only 13% of the initial current after prolonged use. The bioelectrode was electrocatalytically active in the reduction of hydrogen peroxide. On the other hand, the electrodes prepared only by using PEHAA, without catalase, were found to be unresponsive, indicating that the catalytic response is due to catalase and not to PEHAA. However, the presence of the ionic liquid (IL) is fundamental for the immobilization of the enzyme. Consequently, these results indicated that the developed bioelectrodes, based on catalase and PEHAA, are very promising to application as biosensor devices. Graphical abstract Unlabelled Image Highlights • A novel protic ionic liquid (PEHAA) was synthesized and characterized. • A bioelectrode was prepared by assembling catalase and PEHAA on glassy carbon. • The bioelectrode was constructed by the combination of simple and low cost method. • The bioelectrode has shown efficient response for H 2 O 2 reduction. • The presence of PEHAA was essential for the enzyme immobilization. [ABSTRACT FROM AUTHOR]

Highlights • Solutol/α-CD forms poly(pseudo)rotaxane instantaneously maintaining drug solubility. • Soluplus/α-CD interactions require 48 h and decrease drug solubility. • PEG distribution in the copolymer determines poly(pseudo)rotaxanes structure. • Soluplus poly(pseudo)rotaxane dispersions showed viscoelastic behavior. • Drug release was modulated by formation of soluble/insoluble poly(pseudo)rotaxanes. Abstract This work aimed to design supramolecular gels combining Soluplus or Solutol and alfa- and hydroxypropyl-β-cyclodextrin (α-CD, HPβ-CD) for carvedilol (CAR) transdermal delivery. Poly(pseudo)rotaxane formation (appearance, SEM, 1H NMR), drug solubilization, rheological properties and in vitro release were investigated. CAR-CD complexes were prepared in situ or by spray drying. For Solutol, poly(pseudo)rotaxanes were formed immediately after mixing with α-CD and did not influence CAR solubility. Differently, Soluplus poly(pseudo)rotaxanes took 24–48 h to be formed and CAR solubility decreased compared to Soluplus micelles. Soluplus 20% + α-CD (5–10%) showed higher G' and G'’ but also faster CAR release than Solutol poly(pseudo)rotaxanes, which is explained by the different location of PEG chains in the two amphiphilic polymers. Faster drug release was achieved incorporating HPβ-CD or CAR-HPβ-CD spray-dried complexes. The results evidenced the versatility of the formulations in terms of rheological behavior and drug release patterns, which can be adjusted for CAR transdermal delivery. [ABSTRACT FROM AUTHOR]

The paper deals with the mechanical behaviour of a natural volcanic silty soil sampled from steep slopes. This soil is very loose and unsaturated over most of the year due to climate conditions. Thus so-called wetting collapse and static liquefaction may occur during rainfall. Major issues are posed once the slides turn into flows with high destructive potential. However, the modelling of the constitutive behaviour is challenging and not yet available in the literature for this soil. A recent Generalized Plasticity Model was selected as it is capable to adequately take into account the effects of change in soil porosity, bonding related to the matric suction normalized versus soil porosity, and static liquefaction proneness. The model is calibrated for 37 saturated/unsaturated laboratory tests, and the performance of the model is assessed quantitatively. It is newly shown that the model – with one single set of constitutive parameters – is capable to well describe the soil mechanical response, in unsaturated and saturated conditions, experienced by the soil in different laboratory devices and along different stress paths. Those insights provide a theoretical framework for designing further laboratory tests, improving the understanding of this complex natural soil, and implementing better modelling of landslides of the flow-type. [ABSTRACT FROM AUTHOR]

Abstract: The clinical efficacy of antipsychotic drugs has been associated with a certain binding profile for a set of G protein-coupled receptors (GPCR)s. In this work, we use the structurally-related clozapine–olanzapine pair to progress in the understanding of the structural properties that determine their divergent binding profiles and, thereby, their differing therapeutic efficacy. First, we present novel site-directed mutagenesis results that confirm our previous hypothesis on the importance of ligand interaction with positions 5.42 and 5.46 in transmembrane helix 5. Then, we use refined models of ligand-receptor complexes, built from recently published GPCR crystal structures, to gain further insight into the molecular mechanisms responsible for the observed experimental outcomes. In particular, we observe that preventing or potentiating hydrogen bonding with position 5.46, could allow obtaining ligands with, respectively, clozapine or olanzapine-like affinities. Results presented in this study could guide the design of antipsychotic candidates with tailored binding profiles. [Copyright &y& Elsevier]

Highlights: [•] Scientific competency questions define current needs for data integration. [•] Top-ranked questions aim for compound–target relations. [•] Open PHACTS enables semantic integration of public databases for drug discovery research. [Copyright &y& Elsevier]

Abstract: Zein is a protein containing a large amount of nonpolar amino acids, which has shown the ability to form aggregates and entrap solutes, such as drugs and amino acids. NMR techniques were used to detect binding interactions and measure affinity between zein and three different drugs: tetracycline, amoxicillin and indomethacin. The release study of zein microparticle formulations containing any of these drugs was confronted with the affinity results, showing a remarkable correlation. The feasible methodology employed, focused in the functionality of the protein–drug interaction, can be very promising for the rational design of appropriate drug vehicles for drug delivery. [Copyright &y& Elsevier]

Abstract: The intracellularly-occurring Cu(I)–glutathione complex (Cu(I)–[GSH]2) has the ability to reduce molecular oxygen into superoxide. Removal of such radicals leads to the irreversible conversion of Cu(I)–[GSH]2 into the redox-inactive Cu(II)–GSSG complex. The present study addressed the potential of reduced glutathione, ascorbate and superoxide to reductively regenerate Cu(I)–[GSH]2 from Cu(II)–GSSG, and investigated the redox changes involved in such process. Results show that: (i) among the three tested reductants, only GSH is able to reduce the Cu(II) bound to GSSG; (ii) during the reduction of Cu(II)–GSSG, a Cu(I)–GSSG intermediate would be formed (supported here by Cu(I) and GSSG recovery data and by NMR studies); (iii) when GSH is present in a molar excess equal or greater than 1:3, the reduction of Cu(II)–GSSG into Cu(I)–[GSH]2 is quantitative and complete. Under such conditions, the Cu(II)–GSSG complex acquires a superoxide-generating capacity which is identical to that seen with the Cu(I)–[GSH]2 complex. Within cells, the concentrations of GSH are at least 2- to 3-fold order of magnitude higher than those expected for the Cu(II)–GSSG complex. Thus, we postulate that the interaction between GSH and Cu(II)–GSSG could be seen as a potential mechanism to regenerate continuously the Cu(I)–[GSH]2 complex and thereby affect the ability of the latter to generate superoxide. [Copyright &y& Elsevier]

Abstract: A series of new benzolactam derivatives was synthesized and the derivatives were evaluated for their affinities at the dopamine D1, D2, and D3 receptors. Some of these compounds showed high D2 and/or D3 affinity and selectivity over the D1 receptor. The SAR study of these compounds revealed structural characteristics that decisively influenced their D2 and D3 affinities. Structural models of the complexes between some of the most representative compounds of this series and the D2 and D3 receptors were obtained with the aim of rationalizing the observed experimental results. Moreover, selected compounds showed moderate binding affinity on 5-HT2A which could contribute to reducing the occurrence of extrapyramidal side effects as potential antipsychotics. [Copyright &y& Elsevier]

Abstract: The aim of the present work was to characterize a lead compound displaying relevant multi-target interactions, and with an in vivo behavioral profile predictive of atypical antipsychotic activity. Synthesis, molecular modeling and in vitro and in vivo pharmacological studies were carried out for 2-[4-(6-fluorobenzisoxazol-3-yl)piperidinyl]methyl-1,2,3,4-tetrahydro-carbazol-4-one (QF2004B), a conformationally constrained butyrophenone analogue. This compound showed a multi-receptor profile with affinities similar to those of clozapine for serotonin (5-HT2A, 5-HT1A, and 5-HT2C), dopamine (D1, D2, D3 and D4), alpha-adrenergic (α1, α2), muscarinic (M1, M2) and histamine H1 receptors. In addition, QF2004B mirrored the antipsychotic activity and atypical profile of clozapine in a broad battery of in vivo tests including locomotor activity (ED50 =1.19mg/kg), apomorphine-induced stereotypies (ED50 =0.75mg/kg), catalepsy (ED50 =2.13mg/kg), apomorphine- and DOI (2,5-dimethoxy-4-iodoamphetamine)-induced prepulse inhibition (PPI) tests. These results point to QF2004B as a new lead compound with a relevant multi-receptor interaction profile for the discovery and development of new antipsychotics. [Copyright &y& Elsevier]