Multi-parameter optimization: Development of a morpholin-3-one derivative with an improved kinetic profile for imaging monoacylglycerol lipase in the brain

Monoacylglycerol lipase (MAGL) is a gatekeeper in regulating endocannabinoid signaling and has gained sub-stantial attention as a therapeutic target for neurological disorders. We recently discovered a morpholin-3-one derivative as a novel scaffold for imaging MAGL via positron emission tomography (PET). However, its slow kinetics in vivo hampered the application. In this study, structural optimization was conducted and eleven novel MAGL inhibitors were designed and synthesized. Based on the results from MAGL inhibitory potency, in vitro metabolic stability and surface plasmon resonance assays, we identified compound 7 as a potential MAGL PET tracer candidate. [11C]7 was synthesized via direct 11CO2 fixation method and successfully mapped MAGL dis-tribution patterns on rodent brains in in vitro autoradiography. PET studies in mice using [11C]7 demonstrated its improved kinetic profile compared to the lead structure. Its high specificity in vivo was proved by using MAGL KO mice. Although further studies confirmed that [11C]7 is a P-glycoprotein (P-gp) substrate in mice, its low P-gp efflux ratio on cells transfected with human protein suggests that it should not be an issue for the clinical translation of [11C]7 as a novel reversible MAGL PET tracer in human subjects. Overall, [11C]7 ([11C] RO7284390) showed promising results warranting further clinical evaluation.Molecular Physiolog

Portable Platform For Rapid And Indirect Photometric Determination Of Water In Ethanol Fuel Samples

We have developed a simple, fast, portable, inexpensive, and indirect method for the determination of water in ethanol fuels. The addition of an excess amount of water is the most simple and common method of adulterating these fuels. Such procedure can adversely affect the performance of the vehicle. Our system uses a laboratory-made photometry device to monitor the formation of complexes between ethanol and cerium(iv). These reactions produce deep orange-red solutions. The limit of detection and the analytical sensitivity were estimated to be 0.22% v/v (water in ethanol) and 0.11 (% v/v)-1, respectively. The developed platform was satisfactorily robust with respect to the changes in temperature and stability of the reagents during storage. The measurements were accurate at the 95% confidence level compared with data obtained by Karl Fischer titration.62394979502Decicco, J.M., (2012) Clim. Change, 111, p. 627Gnansounou, E., Dauriat, A., Villegas, J., Panichelli, L., (2009) Bioresour. Technol., 100, p. 4919http://ethanolrfa.org/pages/World-Fuel-Ethanol-Production, accessed in April 2014Ribeiro, M.S., Angnes, L., Rocha, F.R.P., (2013) J. Braz. Chem. Soc., 24, p. 418Carneiro, H.S.P., Medeiros, A.R.B., Oliveira, F.C.C., Aguiar, G.H.M., Rubim, J.C., Suarez, P.A.Z., (2008) Energy Fuels, 22, p. 2767Freitas, L.C., Kaneko, S., (2011) Energy Economics, 33, p. 1146Bueno, L., Paixão, T.R.L.C., (2011) Talanta, 87, p. 210Figueiredo, M.K.-K., Costa-Felix, R.P.B., Maggi, L.E., Alvarenga, A.V., Romeiro, G.A., (2012) Fuel, 91, p. 209Silva, A.C., Ponte, L.F.B.L., Pimentel, M.F., Pontes, M.J.C., (2012) Talanta, 93, p. 129http://www.anp.gov.br/, accessed in August 2013http://nxt.anp.gov.br/nxt/gateway.dll/leg/resolucoes_anp, accessed in June 2014http://www.sindalcool.com.br/qualidade, accessed in June 2014Cho, S., Chung, H., Woo, Y., Kim, H., (2005) Bull. Korean Chem. Soc., 26, p. 115Guchardi, R., Pasquini, C., (2001) Appl. Spectrosc., 55, p. 454De Oliveira, W.A., Pasquini, C., (1984) Talanta, 31, p. 82Pereira, P.F., Sousa, R.M.F., Munoz, R.A.A., Richter, E.M., (2013) Fuel, 103, p. 725Omido, C.R., Oliveira, S.L., Shiraishi, R.S., Magalhães, K.F., Ferreira, V.S., De Carvalho, A.A., Kitano, C., De Paula, M.H., (2013) Sens. Actuators, B, 178, p. 581Xiong, F.B., Sisler, D., (2010) Opt. Commun., 283, p. 1326Pereira, A.C., Reis, B.F., Rocha, F.R.P., Talanta, 131, p. 21. , 2015Matkovich, C.F., Christian, G.D., (1972) Anal. Chim. Acta, 60, p. 319Kagevall, I., Aström, O., Cedergren, A., (1981) Anal. Chim. Acta, 132, p. 215Pinyou, P., Youngvises, N., Jakmunee, J., (2011) Talanta, 84, p. 745Reid, B.V.W., Truelove, R.K., (1952) Analyst, 77, p. 325Briois, V., Lützenkirchen-Hecht, D., Villain, F., Fonda, E., Belin, S., Griesebock, B., Frahm, R., (2005) J. Phys. Chem. A, 109, p. 320Suzuki, Y., Aruga, T., Kuwahara, H., Kitamura, M., Kuwabara, T., Kawakubo, S., Iwatsuki, M., (2004) Anal. Sci., 20, p. 975Ellerbee, A.K., Phillips, S.T., Siegel, A.C., Mirica, K.A., Martinez, A.W., Striehl, P., Jain, N., Whitesides, G.M., (2009) Anal. Chem., 81, p. 8447Harris, D.C., (2010) Quantitative Chemical Analysis, , 8th edn, W. H. Freeman and Company, New YorkDoyle, M.P.J., (1974) Chem. Educ., 51, p. 2Young, L.B., Trahanovsky, W.S., (1969) J. Am. Chem. Soc., 91, p. 5060Ribeiro, F.A.L., Ferreira, M.M.C., Morano, S.C., Silva, L.R., Schneider, R.P., (2008) Quim. Nova, 31, p. 164Munoz, R.A.A., Richter, E.M., De Jesus, D.P., Do Lago, C.L., Angnes, L., (2004) J. Braz. Chem. Soc., 15, p. 523Vieira, E.G., Soares, I.V., Dias Filho, N.L., Da Silva, N.C., Garcia, E.F., Bastos, A.C., Perujo, S.D., Faceto, L.F., (2013) J. Colloid Interface Sci., 391, p. 11

INTEGRAÇÃO DE AÇÕES NA GESTÃO SUSTENTÁVEL

A sociedade, afetada pelas desigualdades, pela pobreza e pela fome, dentre outras mazelas, forma um quadro que não pode mais ser desconsiderado pelas organizações. As ações por proteção ambiental e justiça social podem se articular na medida em que esses contextos se completam e têm em comum um objetivo final. As empresas evitam investir em tratamento e em incineração de resíduos, uma vez que podem descartá-los em áreas desvalorizadas, abandonadas pelos investimentos públicos em infraestrutura urbana, e habitadas por populações pobres e menos organizadas. O artigo propõe uma estrutura de referência cujos elementos buscam identificar o compromisso empresarial com a questão socioambiental, aqui denominada Gestão Sustentável Integrada (GSI). Esta se compõe de três planos interdependentes: responsabilidade social corporativa, gestão ambiental e marketing ambiental, todas apoiadas na educação socioambiental. A identificação das ações representativas em cada face ocorreu com abordagem exploratória com consulta a dados secundários, extraídos principalmente das publicações do Instituto Ethos, e das normas brasileiras (NBR) ISO 14.001 e ISO 14.004. Consulta envolvendo 15 especialistas em meio ambiente originou a classificação ordinal das ações relevantes para cada face da GSI, tendo-se concluído que: 1) as ações de responsabilidade social estão vinculadas primordialmente à transparência na gestão; 2) na gestão ambiental, significa racionalizar produtos, processos e serviços da empresa; 3) o marketing ambiental deve se concentrar na seleção de fornecedores, concepção de projetos e de inovações que mitiguem o impacto ambiental

CMS physics technical design report: Addendum on high density QCD with heavy ions

This report presents the capabilities of the CMS experiment to explore the rich heavy-ion physics programme offered by the CERN Large Hadron Collider (LHC). The collisions of lead nuclei at energies ,will probe quark and gluon matter at unprecedented values of energy density. The prime goal of this research is to study the fundamental theory of the strong interaction - Quantum Chromodynamics (QCD) - in extreme conditions of temperature, density and parton momentum fraction (low-x). This report covers in detail the potential of CMS to carry out a series of representative Pb-Pb measurements. These include "bulk" observables, (charged hadron multiplicity, low pT inclusive hadron identified spectra and elliptic flow) which provide information on the collective properties of the system, as well as perturbative probes such as quarkonia, heavy-quarks, jets and high pT hadrons which yield "tomographic" information of the hottest and densest phases of the reaction.0info:eu-repo/semantics/publishe