Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic Activity

Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl) benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenyl-ethynyl)-pyridine (MPEP) binding site. VU0285683 had anxiolytic-like activity in two rodent models for anxiety but did not potentiate phen-cyclidine-induced hyperlocomotor activity. (4-Hydroxypiperidin-1-yl)(4-phenylethynyl) phenyl) methanone (VU0092273) was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, N-cyclobutyl-6-((3-fluorophenyl) ethynyl) nicotinamide hydrochloride (VU0360172), which is selective for mGluR5. This novel mGluR5 PAM produced a dose-dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of antipsychotic activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in the treatment of CNS disorders.

S-(2-Succinyl)cysteine:a novel chemical modification of tissue proteins by a Krebs cycle intermediate

S-(2-Succinyl)cysteine (2SC) has been identified as a chemical modification in plasma proteins, in the non-mercaptalbumin fraction of human plasma albumin, in human skin collagen, and in rat skeletal muscle proteins and urine. 2SC increases in human skin collagen with age and is increased in muscle protein of diabetic vs. control rats. The concentration of 2SC in skin collagen and muscle protein correlated strongly with that of the advanced glycation/lipoxidation end-product (AGE/ALE), N(epsilon)-(carboxymethyl)lysine (CML). 2SC is formed by a Michael addition reaction of cysteine sulfhydryl groups with fumarate at physiological pH. Fumarate, but not succinate, inactivates the sulfhydryl enzyme, glyceraldehyde-3-phosphate dehydrogenase in vitro, in concert with formation of 2SC. 2SC is the first example of spontaneous chemical modification of protein by a metabolic intermediate in the Krebs cycle. These observations identify fumarate as an endogenous electrophile and suggest a role for fumarate in regulation of metabolism.

Universal tight binding model for chemical reactions in solution and at surfaces. II. Water

A revised water model intended for use in condensed phase simulations in the framework of the self consistent polarizable ion tight binding theory is constructed. The model is applied to water monomer, dimer, hexamers, ice, and liquid, where it demonstrates good agreement with theoretical results obtained by more accurate methods, such as DFT and CCSD(T), and with experiment. In particular, the temperature dependence of the self diffusion coefficient in liquid water predicted by the model, closely reproduces experimental curves in the temperature interval between 230 K and 350 K. In addition, and in contrast to standard DFT, the model properly orders the relative densities of liquid water and ice. A notable, but inevitable, shortcoming of the model is underestimation of the static dielectric constant by a factor of two. We demonstrate that the description of inter and intramolecular forces embodied in the tight binding approximation in quantum mechanics leads to a number of valuable insights which can be missing from ab initio quantum chemistry and classical force fields. These include a discussion of the origin of the enhanced molecular electric dipole moment in the condensed phases, and a detailed explanation for the increase of coordination number in liquid water as a function of temperature and compared with ice-leading to insights into the anomalous expansion on freezing. The theory holds out the prospect of an understanding of the currently unexplained density maximum of water near the freezing point. 

Effect of nanosilica addition on the fresh properties and shrinkage of mortars with fly ash and superplasticizer

The ongoing use of various mineral additions along with chemical admixtures such as superplasticizers justifies the need for further research. Understanding and quantifying their effects and possible synergies on the fresh and hardened properties of cement-based materials is necessary, especially if some of these components are known to have a pozzolanic effect. This paper describes and models the fresh and hardened properties of cement mortars including nanosilica and fly ash, and relates their properties to the proportioning of these materials and the superplasticizer dosage. Mini-slump, Marsh cone and Lombardi cone tests were used to examine the properties of the fresh mortars, and to assess density, plastic shrinkage, and drying shrinkage up to 20 days. The equations presented in this paper make it possible to optimize mortar proportionings to the required levels of performance in both fresh and hardened states.

Electrochemical promotion of catalysis controlled by chemical potential difference across a mixed ionic-electronic conducting ceramic membrane - An example of wireless NEMCA

A La_0.6Sr_0.4Co_0.2F_0.8O₃ mixed ionic electronic conducting (MIEC) membrane was used in a dual chamber reactor for the promotion of the catalytic activity of a platinum catalyst for ethylene oxidation. By controlling the oxygen chemical potential difference across the membrane, a driving force for oxygen ions to migrate across the membrane and backspillover onto the catalyst surface is established. The reaction is then promoted by the formation of a double layer of oxide anions on the catalyst surface. Thelectronic conductivity of the membrane material eliminates the need for an external circuit to pump the promoting oxide ion species through the membrane and onto the catalyst surface. This renders this "wireless" system simpler and more amenable for large-scale practical application. Preliminary experiments show that the reaction rate of ethylene oxidation can indeed be promoted by almost one order of magnitude upon exposure to an oxygen atmosphere on the sweep side of the membrane reactor, and thus inducing an oxygen chemical potential difference across the membrane, as compared to the rate under an inert sweep gas. Moreover, the rate does not return to its initial unpromoted value upon cessation of the oxygen flow on the sweep side, but remains permanently promoted. A number of comparisons are drawn between the classical electrochemical promotion that utilises an external circuit and the "wireless" system that utilises chemical potential differences. In addition a 'surface oxygen capture' model is proposed to explain the permanent promotion of the catalyst activity. © 2007 Springer Science+Business Media, LLC.

The addition of CO2 to four superbase ionic liquids: a DFT study

The addition of carbon dioxide to four superbase ionic liquids, [P3333][Benzim], [P3333][124Triz], [P3333][123Triz] and [P3333][Bentriz] was studied using a molecular DFT approach involving anions alone and individual ion pairs. Intermolecular bonding within the individual ion pairs is characterised by a number of weak hydrogen bonds, with the superbase anion geometrically arranged so as to maximize interactions between the heterocyclic N atoms and the cation. The pairing energies show no correlation to the observed CO2 adsorption capacity. Addition of CO2 to the anion alone clearly resulted in the formation of a covalently-bound carbamate function with the strength of binding correlated to experimental capacity. In the ion pair however the cation significantly alters the nature of the bonding such that the overall cohesive energy is reduced. Formation of a strong carbamate function occurs at the expense of weakening the interaction between anion and cation. In the more weakly absorbing ion pairs which contain [123Triz]- and [Bentriz]-, the carbamate-functionalised systems are very close in energy to adducts in which CO2 is more weakly bound, suggesting an equilibrium between the chemi- and physisorbed CO2.

Combined effects of chemical and natural stressors to soil organisms and plants

Nas últimas décadas, a Terra tem experimentado um aquecimento global e mudanças nos padrões de precipitação. Muitos estudos sobre a avaliação de risco de agrotóxicos em organismos não-alvo foram realizados com base em protocolos padronizados, com condições abióticas controladas. Mas, em campo, os organismos são expostos a flutuações de vários fatores ambientais, bem como a poluentes, que podem alterar os limites de tolerância dos organismos aos stressores naturais, bem como alterar a toxicidade ou biodisponibilidade do químico em causa. Considerando isso, o principal objetivo deste trabalho foi o de avaliar de que modo e em que medida os fatores ambientais (temperatura, humidade do solo e radiação UV) podem interagir uns com os outros ou afetar a toxicidade do carbaril para invertebrados do solo e plantas. Para isso, foram utilizadas quatro espécies padrão: Folsomia candida, Eisenia andrei, Triticum aestivum e Brassica rapa, e simulados diferentes cenários climáticos, com vários parâmetros letais e subletais analisados. A exposição combinada foi analisada utilizando, quando possível, a ferramenta MIXTOX, com base no modelo de referência de acção independente (IA) e possíveis desvios, assim como rácios sinergísticos/antagonísticos (a partir de valores de EC50/LC50), quando a dose-resposta de um dos stressores não foi obtida. Todos os fatores de stress aplicados isoladamente causaram efeitos significativos sobre as espécies testadas e sua exposição combinada com carbaril, apresentaram respostas diferenciadas: para as minhocas, a seca e temperaturas elevadas aumentaram os efeitos deletérios do carbaril (sinergismo), enquanto o alagamento e temperaturas baixas diminuíram sua toxicidade (antagonismo). Para os colêmbolos, o modelo IA mostrou ser uma boa ferramenta para prever a toxicidade do carbaril tanto para temperaturas altas como para as baixas. Para as duas espécies de plantas foram encontradas diferenças significativas entre elas: em termos gerais, as interações entre carbaril e os stressores naturais foram observadas, com sinergismo aparecendo como o padrão principal relacionado com a radiação UV, solos secos e temperaturas elevadas, enquanto o padrão principal relacionado com temperaturas baixas e stress de alagamento foi o antagonismo. Quando os efeitos de dois stressores naturais (radiação UV e humidade do solo) em plantas foram avaliados, uma interação significativa foi encontrada: a seca aliviou o efeito deletério da radiação UV em T. aestivum e o alagamento aumentou os seus efeitos, mas para B. rapa a adição de ambos os stresses de água causou um aumento (sinergismo) dos efeitos deletérios da radiação UV para todos os parâmetros avaliados. Portanto é necessário que as diferenças sazonais e latitudinais, bem como as mudanças climáticas globais, sejam integradas na avaliação de risco de contaminantes do solo.

Chemical communication in the Mozambique tilapia: a role for amino acids

The Mozambique tilapia (Oreochromis mossambicus) is a maternal mouthbrooding cichlid from the southern Africa. The olfactory sensitivity of the species to 20 amino acids was assessed using the electro-olfactogram (EOG). We estimated whether the olfactory potency of the polar fraction of male urine can be explained by the presence of identified amino acids. In addition, filtrate and amino acid mixture of the urine of Nile tilapia were used to estimate their olfactory potency for O.mossambicus. Finally, concentrations of the main amino acids were measured in the urine of males of different social status and the correlations between amino acid concentration and hierarchical status were explored. L-cysteine, L-glutamine and L-threonine were the most potent stimuli at M while L-proline and L-aspartate were the least potent. Four groups of amino acids were identified according to their thresholds of detection and three groups – according to the similarity of their ɣ-factors. The estimated threshold of detection for O.mossambicus mixture was higher than that for the filtrate. On the contrary, the threshold of detection for the mixture of Nile tilapia was lower than that for the filtrate The concentration of L-arginine in the urine was positively correlated with fish dominance index. Both L-arginine and L-glutamic acid concentrations had much greater variability in dominant males (DI˃0.5) than in subordinate males (DI˂0.5). The urinary concentrations of L-phenylalanine had similar variability in dominant and subordinate groups. The Mozambique tilapia has olfactory sensitivity to all twenty amino acids tested. The fish showed more acute sensitivity to conspecific urine filtrate than to the heterospecific. Olfactory potency of O.mossambicus filtrate can be largely but not fully explained by the presence of L-arginine, L-glutamic acid and L-phenylalanine. Larginine and L-glutamic acid may indicate the dominance status of the fish and, possibly, individual identity.

Sustainable Chemical Regulation in a Global Environment

The globalisation and unintended impacts of chemicals sets substantial challenges for sustainable development and the protection of natural resources such as land and water. Currently, there are three key chemical Conventions, the Basel Convention on the Control of Transboundary Movements of Hazardous Wastes and their Disposal which came into force in 1992, the 1993 Rotterdam Convention on Trade in Dangerous Chemicals and the Stockholm Convention on Persistent Organic Pollutants (POPs) (2004). These Conventions have as common features a mechanism for assessment of chemical safety, a process for the addition of new chemicals to a list of controlled substances and capacity building in developed countries. However, they only cover a small fraction of the chemicals manufactured and traded across the world. Defining effective regulation of chemicals is an on-going debate that has the potential to have a significant impact on vested commercial and political interests. A sustainable chemical industry should take account of evidence-based standards and through legal mechanisms adopt long-term precautionary evaluations rather than short-term market driven decisions. It is argued in this paper that effective international chemical regulation in the future will come from the adoption of sound chemical management and corporate social responsibility, but it recognised that this will face the challenge of economic disparity between countries and the potential export of regulatory risk from big chemical conglomerates to poorly regulated jurisdictions.

Impact of prescribed fire on the chemical properties of soil

Prescribed fire is a common forest management tool used in Portugal to reduce the fuel load availability and minimize the occurrence of wildfires. In addition, the use of this technique also causes an impact to ecosystems. In this presentation we propose to illustrate some results of our project in two forest sites, both located in Northwest Portugal, where the effect of prescribed fire on soil properties were recorded during a period of 6 months. Changes in soil moisture, organic matter, soil pH and iron, were examined by Principal Component Analysis multivariate statistics technique in order to determine impact of prescribed fire on these soil properties in these two different types of soils and determine the period of time that these forest soils need to recover to their pre-fire conditions, if they can indeed recover. Although the time allocated to this study does not allow for a widespread conclusion, the data analysis clearly indicates that the pH values are positively correlated with iron values at both sites. In addition, geomorphologic differences between both sampling sites, Gramelas and Anjos, are relevant as the soils’ properties considered have shown different performances in time. The use of prescribed fire produced a lower impact in soils originated from more amended bedrock and therefore with a ticker humus covering (Gramelas) than in more rocky soils with less litter covering (Anjos) after six months after the prescribed fire occurrence.

Space and time characterization of laser-induced plasmas for applications in chemical analysis and thin film deposition

Après des décennies de développement, l'ablation laser est devenue une technique importante pour un grand nombre d'applications telles que le dépôt de couches minces, la synthèse de nanoparticules, le micro-usinage, l’analyse chimique, etc. Des études expérimentales ainsi que théoriques ont été menées pour comprendre les mécanismes physiques fondamentaux mis en jeu pendant l'ablation et pour déterminer l’effet de la longueur d'onde, de la durée d'impulsion, de la nature de gaz ambiant et du matériau de la cible. La présente thèse décrit et examine l'importance relative des mécanismes physiques qui influencent les caractéristiques des plasmas d’aluminium induits par laser. Le cadre général de cette recherche forme une étude approfondie de l'interaction entre la dynamique de la plume-plasma et l’atmosphère gazeuse dans laquelle elle se développe. Ceci a été réalisé par imagerie résolue temporellement et spatialement de la plume du plasma en termes d'intensité spectrale, de densité électronique et de température d'excitation dans différentes atmosphères de gaz inertes tel que l’Ar et l’He et réactifs tel que le N2 et ce à des pressions s’étendant de 10‾7 Torr (vide) jusqu’à 760 Torr (pression atmosphérique). Nos résultats montrent que l'intensité d'émission de plasma dépend généralement de la nature de gaz et qu’elle est fortement affectée par sa pression. En outre, pour un délai temporel donné par rapport à l'impulsion laser, la densité électronique ainsi que la température augmentent avec la pression de gaz, ce qui peut être attribué au confinement inertiel du plasma. De plus, on observe que la densité électronique est maximale à proximité de la surface de la cible où le laser est focalisé et qu’elle diminue en s’éloignant (axialement et radialement) de cette position. Malgré la variation axiale importante de la température le long du plasma, on trouve que sa variation radiale est négligeable. La densité électronique et la température ont été trouvées maximales lorsque le gaz est de l’argon et minimales pour l’hélium, tandis que les valeurs sont intermédiaires dans le cas de l’azote. Ceci tient surtout aux propriétés physiques et chimiques du gaz telles que la masse des espèces, leur énergie d'excitation et d'ionisation, la conductivité thermique et la réactivité chimique. L'expansion de la plume du plasma a été étudiée par imagerie résolue spatio-temporellement. Les résultats montrent que la nature de gaz n’affecte pas la dynamique de la plume pour des pressions inférieures à 20 Torr et pour un délai temporel inférieur à 200 ns. Cependant, pour des pressions supérieures à 20 Torr, l'effet de la nature du gaz devient important et la plume la plus courte est obtenue lorsque la masse des espèces du gaz est élevée et lorsque sa conductivité thermique est relativement faible. Ces résultats sont confirmés par la mesure de temps de vol de l’ion Al+ émettant à 281,6 nm. D’autre part, on trouve que la vitesse de propagation des ions d’aluminium est bien définie juste après l’ablation et près de la surface de la cible. Toutefois, pour un délai temporel important, les ions, en traversant la plume, se thermalisent grâce aux collisions avec les espèces du plasma et du gaz.

Chemical and Biochemical Studies on Natural Antioxidants from sesamum Species

In the present study on natural antioxidants, the focus has been kept mainly on oil seeds, especially sesame and its by-products. Sesame, which has been under cultivation in India for centuries is called the 'Queen of oil seed crops' because of the high yield of oil obtained and the nutritional qualities of the seed, oil, and meal. Though India is the largest producer of sesame in the world, research on the various health benefits of sesame has been carried out by Japanese Sesame has an important place in the foods and tradit..ional medicine of India from time immemorial. Foreseeing the potential of sesame and its byproducts as an important antioxidant source and its availability in bulk, the present study was focussed on Sesamum species. There are not many reports on the wild species of Sesamum in India, especially of the Kerala region. Hence, in the present study we also included antioxidants of Sesamurnrnalabaricumdistributed throughout the coastal region.The important characteristics of sesame are attributed to the presence of the umquc compounds lignans. Lignans arc a group of natural products of phenyl propanoid ongm, whieh are widely distributed in nature. They display important physiological functions in plants, in human nutrition and medicine, given their extensive health promotive and curative properties. Much interest has been focussed on their effectiveness as antineoplastic agents and research in this area has revealed several modes of action by which they can regulate the growth of mammalian cells. Sesame is an important source of furofuran lignans, of which sesamin and the rare oxygenated derivative sesamoIin are the most abundant. Others include sesamol and glucosides of lignans. Sesarnin and episesamin are reported to have hypocholesterolemic effect, suppressive effect on chemically induced cancer, alleviation of allergy symptoms etc. Sesamol, sesamolin and the lignan glycosides are reported to inhibit lipid peroxidation. Present investigation on sesame and its byproducts have been carried out to explore the possibility of developing a natural antioxidant extract from available resources to be used as a substitute to synthetic ones in vegetable oils and foods. Preliminary analysis showed that sesame cake, a byproduct could still be utilized as a major source of lignans. Sesame cake, which is now used only as a cattlefeed, can be better utilized in the form of a valuable antioxidant source. The present study explains the development of a feasible process for the extraction of antioxidant compounds from sesame cake. The antioxidant extract so prepared from sesame cake has been tested for vegetable oil protection and is found to be effective at low concentration. In addition, studies also include the antioxidant, radical scavenging, anticancer, mosquitocidal and pesticidal activities of extract and individual compounds.

An investigation on the effects of Ag addition in the powder — in tube processing of long multifilamentary (Bi,Pb) - 2223/Ag superconducting tapes

It is important that long superconducting tape must have desired strain tolerance (less reduction of Jc with applied strains) and stress tolerance (less reduction of JC in applied stresses) for its use as coils and magnets. Ag addition to the BPSCCO system has many advantages with its physical and chemical inertness to the system, reduces the processing temperature, and promotes the grain growth, grain alignment and connectivity. All these not only enhance the critical current density of the tapes but also improve the mechanical properties. But the published results show very much scattering on the type of Ag additive to be selected, method of addition and its optimum percentage. Also there are some negative reports in this regard. The present work has been undertaken to study the effect of silver addition in different forms (Ag powder, Ag2O, AgNO3) on the superconducting and mechanical properties of (Bi,Pb)-2223/Ag tapes and to find out a suitable form of Ag additive and its optimum percentage to have better superconducting and mechanical properties. Also it is the aim of the present work is to optimise the process parameters needed to prepare (Bi,Pb)-2223/Ag multifilamentary tapes of length ~ 12 m in solenoid and pancake coil forms with good critical current density and homogeneity of J C along the length of the tapes.