Enlaces de hidrógeno bifuncionales >O...H(H)...H-C en el complejo tetrahidrofurano-agua. Un estudio teórico

En este trabajo se estudia el enlace de hidrógeno bifuncional, EHbif, en el complejo THFH2O en fase gaseosa, en el marco de la Teoría del funcional de la densidad. Los cálculos de estructura electrónica se llevaron a cabo utilizando el funcional híbrido B3LYP y el conjunto base 6-31G**. Para realizar un estudio electrónico profundo de las interacciones intra e intermoleculares involucradas en el EH bifuncional, el análisis de transferencia de carga sobre la base de Orbitales Naturales de Enlace, NBO, fue llevado adelante en forma conjunta con la aplicación de la Teoría de Atomos en Molécula, AIM. Además de verificarse la formación del EHbif, donde una única molécula de agua interviene como dadora de hidrógeno (Ow-Hw(b)…OTHF) y aceptora de hidrógeno (C4 -H4sa…Ow) en la formación de un (fuerte o moderadamente fuerte) EH propio y otro (débil) EH impropio, respectivamente, se analizan los efectos cooperativos entre los EHs propios e impropios. Los resultados muestran que la redistribución electrónica sobre la molécula completa es la principal característica del complejo THF-H2O. En otras palabras, las modificaciones en la parte remota (Z), en Z-X-H…Y, que según Hobza caracteriza a los EH impropios, ocurre en ambos EH, propio e impropio, como consecuencia de los efectos donador-aceptor intra e intermoleculare

Conformational and electronic intricacies of dopamine interacting with the D2 Dopamine Receptor: A comprehensive theoretical study

Understanding of the biological behavior of different L-R complexes requires determining the conformational and electronic aspects of both the small ligand as well as the binding site of its receptor. Here we report the conformational and electronic behavior of dopamine (DO)  interacting at the active site of the D2 dopamine receptor (D2DR). The selection of this molecular target is due to two main  reasons: it is a molecular target of great importance for medicinal chemistry and very useful structural information has been recently reported due to the D2DR has been crystallized. Different computational techniques have been used in combination in this study. In this way, docking calculations,  molecular dynamics simulations and quantum mechanical calculations have been performed. Moreover, the different molecular interactions of the  complexes were evaluated in detail using two techniques: QTAIM (Quantum Theory of Atoms in Molecules) and NMR nuclear magnetic shielding  constants calculations. Our study goes much further than any previously done, since for the first time we have been able to obtain and report the complete  conformational potential energy surface (PES) for DO in its binding pocket. Analysis of the complete PES is the most comprehensive way to understand the conformational behavior of a ligand such as DO, which possesses two rotatable bonds, since it is possible to locate all critical points on the surface and even see its different conformational inter-conversion paths.Our study indicates that seven different conformations of DO are the most relevant. From these seven ones, two are those that could be  considered as the biologically relevant conformations of DO. On the other hand, the most important molecular interactions that stabilize these molecular complexes are those with Asp80, Val81, Cys84, Thr85, Ser159, Ser160, Ser163, Phe164 and Tyr403.Fil: Goicoechea, Moro L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Tosso, Rodrigo David. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Parravicini, Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Zarycz, Maria Natalia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Angelina, Emilio Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Química Básica y Aplicada del Nordeste Argentino. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas Naturales y Agrimensura. Instituto de Química Básica y Aplicada del Nordeste Argentino; Argentina. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas y Naturales y Agrimensura. Departamento de Química. Laboratorio de Estructura Molecular y Propiedades; ArgentinaFil: Vettorazzi, Marcela Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Andujar, Sebastian Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaFil: Enriz, Ricardo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis. Universidad Nacional de San Luis. Facultad de Ciencias Físico Matemáticas y Naturales. Instituto Multidisciplinario de Investigaciones Biológicas de San Luis; ArgentinaXLVIII Reunión Anual de la Sociedad Argentina de BiofísicaSan LuisArgentinaSociedad Argentina de BiofísicaUniversidad Nacional de San Lui

Tetrahydroisoquinolines functionalized with carbamates as selective ligands of D2 dopamine receptor

[EN] A series of tetrahydroisoquinolines functionalized with carbamates is reported here as highly selective ligands on the dopamine D2 receptor. These compounds were selected by means of a molecular modeling study. The studies were carried out in three stages: first an exploratory study was carried out using combined docking techniques and molecular dynamics simulations. According to these results, the bioassays were performed; these experimental studies corroborated the results obtained by molecular modeling. In the last stage of our study, a QTAIM analysis was performed in order to determine the main molecular interactions that stabilize the different ligand-receptor complexes. Our results show that the adequate use of combined simple techniques is a very useful tool to predict the potential affinity of new ligands at dopamine D1 and D2 receptors. In turn the QTAIM studies show that they are very useful to evaluate in detail the molecular interactions that stabilize the different ligand-receptor complexes; such information is crucial for the design of new ligands.This work was supported by Universidad Nacional de San Luis (UNSL) and CONICET grants 2-1214 and PIP444, respectively. E.L.A, L.J.G, S.A.A and R.D.E are staff members of the National Scientific and Technical Research Council - Argentina ( CONICET, Argentina).Parravicini, O.; Bogado, ML.; Rojas, S.; Angelina, EL.; Andujar, SA.; Gutierrez, LJ.; Cabedo Escrig, N.... (2017). Tetrahydroisoquinolines functionalized with carbamates as selective ligands of D2 dopamine receptor. Journal of Molecular Modeling. 23(9):1-14. https://doi.org/10.1007/s00894-017-3441-6S114239Beaulieu JM, Gainetdinov RR (2011) The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev 63(1):182–217. https://doi.org/10.1124/pr.110.002642Luthra PM, Kumar JBS (2012) Plausible improvements for selective targeting of dopamine receptors in therapy of Parkinson’s disease. Mini-Rev Med Chem 12(14):1556–1564. https://doi.org/10.2174/138955712803832645Poewe W (2009) Treatments for Parkinson disease-past achievements and current clinical needs. Neurology 72 (7 SUPPL. 2):S65-S73. https://doi.org/10.1212/WNL.0b013e31819908ceSeeman P, Watanabe M, Grigoriadis D (1985) Dopamine D2 receptor binding sites for agonists: a tetrahedral model. Mol Pharmacol 28(5):391–399McDonald WM, Sibley DR, Kilpatrick BF, Caron MG (1984) Dopaminergic inhibition of adenylate cyclase correlates with high affinity agonist binding to anterior pituitary D2 dopamine receptors. Mol Cell Endocrinol 36(3):201–209. https://doi.org/10.1016/0303-7207(84)90037-6Mottola DM, Laiter S, Watts VJ, Tropsha A, Wyrick SD, Nichols DE, Mailman RB (1996) Conformational analysis of D1 dopamine receptor agonists: pharmacophore assessment and receptor mapping. J Med Chem 39(1):285–296. https://doi.org/10.1021/jm9502100Alkorta I, Villar HO (1993) Considerations on the recognition of the D1 receptor by agonists. J Comput Aided Mol Des 7(6):659–670. https://doi.org/10.1007/BF00125324Cueva JP, Giorgioni G, Grubbs RA, Chemel BR, Watts VJ, Nichols DE (2006) Trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline: synthesis, resolution, and preliminary pharmacological characterization of a new dopamine D1 receptor full agonist. J Med Chem 49(23):6848–6857. https://doi.org/10.1021/jm0604979Negash K, Nichols DE, Watts VJ, Mailman RB (1997) Further definition of the D1 dopamine receptor pharmacophore: synthesis of trans-6,6a,7,8,9,13b-hexahydro-5h-benzo[d]naphth[2,1-b]azepines as rigid analogues of β-phenyldopamine. J Med Chem 40(14):2140–2147. https://doi.org/10.1021/jm970157aPettersson I, Liljefors T (1987) Structure-activity relationships for apomorphine congeners. Conformational energies vs. biological activities. J Comput Aided Mol Des 1(2):143–152. https://doi.org/10.1007/BF01676958Tonani R, Dunbar Jr J, Edmonston B, Marshall GR (1987) Computer-aided molecular modeling of a D2-agonist dopamine pharmacophore. J Comput Aided Mol Des 1(2):121–132. https://doi.org/10.1007/BF01676956Mewshaw RE, Kavanagh J, Stack G, Marquis KL, Shi X, Kagan MZ, Webb MB, Katz AH, Park A, Kang YH, Abou-Gharbia M, Scerni R, Wasik T, Cortes-Burgos L, Spangler T, Brennan JA, Piesla M, Mazandargmi H, Cockett MI, Ochalski R, Coupet J, Andree TH (1997) New generation dopaminergic agents. 1. Discovery of a novel scaffold which embraces the D2 agonist pharmacophore. Structure-activity relationships of a series of 2-(aminomethyl)chromans. J Med Chem 40(26):4235–4256. https://doi.org/10.1021/jm9703653Chidester CG, Lin CH, Lahti RA, Haadsma-Svensson SR, Smith MW (1993) Comparison of 5-HT1A and dopamine D2 pharmacophores. X-ray structures and affinities of conformationally constrained ligands. J Med Chem 36(10):1301–1315Alkorta I, Villar HO (1994) Molecular electrostatic potential of d1 and d2 dopamine agonists. J Med Chem 37(1):210–213Wilcox RE, Tseng T, Brusniak MYK, Ginsburg B, Pearlman RS, Teeter M, Durand C, Starr S, Neve KA (1998) CoMFA-based prediction of agonist affinities at recombinant D1 vs D2 dopamine receptors. J Med Chem 41(22):4385–4399. https://doi.org/10.1021/jm9800292El Aouad N, Berenguer I, Romero V, Marín P, Serrano A, Andujar S, Suvire F, Bermejo A, Ivorra MD, Enriz RD, Cabedo N, Cortes D (2009) Structure-activity relationship of dopaminergic halogenated 1-benzyl-tetrahydroisoquinoline derivatives. Eur J Med Chem 44(11):4616–4621. https://doi.org/10.1016/j.ejmech.2009.06.033Berenguer I, Aouad NE, Andujar S, Romero V, Suvire F, Freret T, Bermejo A, Ivorra MD, Enriz RD, Boulouard M, Cabedo N, Cortes D (2009) Tetrahydroisoquinolines as dopaminergic ligands: 1-butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline, a new compound with antidepressant-like activity in mice. Bioorg Med Chem 17(14):4968–4980. https://doi.org/10.1016/j.bmc.2009.05.079Andujar S, Suvire F, Berenguer I, Cabedo N, Marin P, Moreno L, Dolores Ivorra M, Cortes D, Enriz RD (2012) Tetrahydroisoquinolines acting as dopaminergic ligands. A molecular modeling study using MD simulations and QM calculations. J Mol Model 18(2):419–431. https://doi.org/10.1007/s00894-011-1061-0Angelina E, Andujar S, Tosso RD, Enriz RD, Peruchena N (2014) Non-covalent interactions in receptor–ligand complexes. A study based on the electron charge density. J Phys Org Chem 27:128–134Parraga J, Cabedo N, Andujar S, Piqueras L, Moreno L, Galan A, Angelina E, Enriz RD, Ivorra MD, Sanz MJ, Cortes D (2013) 2,3,9- and 2,3,11-trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands. Eur J Med Chem 68:150–166Andujar SA, de Angel BM, Charris JE, Israel A, Suarez-Roca H, Lopez SE, Garrido MR, Cabrera EV, Visbal G, Rosales C, Suvire FD, Enriz RD, Angel-Guio JE (2008) Synthesis, dopaminergic profile, and molecular dynamics calculations of N-aralkyl substituted 2-aminoindans. Bioorg Med Chem 16(6):3233–3244Párraga J, Andujar SA, Rojas S, Gutierrez LJ, El Aouad N, Sanz MJ, Enriz RD, Cabedo N, Cortes D (2016) Dopaminergic isoquinolines with hexahydrocyclopenta[ij]-isoquinolines as D2−like selective ligands. Eur J Med Chem 122:27-42. https://doi.org/10.1016/j.ejmech.2016.06.009Galán A, Moreno L, Párraga J, Serrano Á, Sanz MJ, Cortes D, Cabedo N (2013) Novel isoquinoline derivatives as antimicrobial agents. Bioorg Med Chem 21(11):3221–3230. https://doi.org/10.1016/j.bmc.2013.03.042Malo M, Brive L, Luthman K, Svensson P (2010) Selective pharmacophore models of dopamine D1 and D2 full agonists based on extended pharmacophore features. ChemMedChem 5(2):232–246. https://doi.org/10.1002/cmdc.200900398Lan H, DuRand CJ, Teeter MM, Neve KA (2006) Structural determinants of pharmacological specificity between D 1 and D2 dopamine receptors. Mol Pharmacol 69(1):185–194. https://doi.org/10.1124/mol.105.017244Neve KA, Cumbay MG, Thompson KR, Yang R, Buck DC, Watts VJ, Durand CJ, Teeter MM (2001) Modeling and mutational analysis of a putative sodium-binding pocket on the dopamine D2 receptor. Mol Pharmacol 60(2):373–381Kalani MYS, Vaidehi N, Hall SE, Trabanino RJ, Freddolino PL, Kalani MA, Floriano WB, Wai Tak Kam V, Goddard Iii WA (2012) The predicted 3D structure of the human D2 dopamine receptor and the binding site and binding affinities for agonists and antagonists. Proc Natl Acad Sci USA 101:3815–3820Becker OM, Marantz Y, Shacham S, Inbal B, Heifetz A, Kalid O, Bar-Haim S, Warshaviak D, Fichman M, Noiman S (2004) G protein-coupled receptors: in silico, drug discovery in 3D. Proc Natl Acad Sci USA 101(31):11304–11309. https://doi.org/10.1073/pnas.0401862101Micheli F, Bonanomi G, Blaney FE, Braggio S, Capelli AM, Checchia A, Curcuruto O, Damiani F, Di Fabio R, Donati D, Gentile G, Gribble A, Hamprecht D, Tedesco G, Terreni S, Tarsi L, Lightfoot A, Stemp G, MacDonald G, Smith A, Pecoraro M, Petrone M, Perini O, Piner J, Rossi T, Worby A, Pilla M, Valerio E, Griffante C, Mugnaini M, Wood M, Scott C, Andreoli M, Lacroix L, Schwarz A, Gozzi A, Bifone A, Ashby Jr CR, Hagan JJ, Heidbreder C (2007) 1,2,4-Triazol-3-yl-thiopropyl-tetrahydrobenzazepines: a series of potent and selective dopamine D3 receptor antagonists. J Med Chem 50(21):5076–5089. https://doi.org/10.1021/jm0705612Párraga J, Cabedo N, Andujar S, Piqueras L, Moreno L, Galán A, Angelina E, Enriz RD, Ivorra MD, Sanz MJ, Cortes D (2013) 2,3,9- and 2,3,11-Trisubstituted tetrahydroprotoberberines as D2 dopaminergic ligands. Eur J Med Chem. 68:150-166. https://doi.org/10.1016/j.ejmech.2013.07.036Angelina E, Andujar S, Moreno L, Garibotto F, Párraga J, Peruchena N, Cabedo N, Villecco M, Cortes D, Enriz RD (2015) 3-chlorotyramine acting as ligand of the D2 dopamine receptor. Molecular modeling, synthesis and D2 receptor affinity. Molec Inform 34 (1):28-43. https://doi.org/10.1002/minf.201400093Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30(16):2785–2791Lindorff-Larsen K, Piana S, Palmo K, Maragakis P, Klepeis JL, Dror RO, Shaw DE (2010) Improved side-chain torsion potentials for the amber ff99SB protein force field. Proteins 78(8):1950–1958. https://doi.org/10.1002/prot.22711Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25(9):1157–1174Case DA, Darden TA, Cheatham III TE, Simmerling CL, Wang J, Duke RE, Luo R, Walker RC, Zhang W, Merz KM, Roberts B, Hayik S, Roitberg A, Seabra G, Swails J, Goetz AW, Kolossváry I, Wong KF, Paesani F, Vanicek J, Wolf RM, Liu J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Cai Q, Ye X, Wang J, Hsieh M-J, Cui G, Roe DR, Mathews DH, Seetin MG, Salomon-Ferrer R, Sagui C, Babin V, Luchko T, Gusarov S, Kovalenko A, Kollman PA (2012) AMBER12. University of California, San FranciscoRyckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23(3):327–341. https://doi.org/10.1016/0021-9991(77)90098-5Izaguirre JA, Catarello DP, Wozniak JM, Skeel RD (2001) Langevin stabilization of molecular dynamics. J Chem Phys 114(5):2090–2098. https://doi.org/10.1063/1.1332996Essmann U, Perera L, Berkowitz M, Darden T, Lee H, Pedersen L (1995) A smooth particle mesh Ewald method. J Chem Phys 103:8577–8593Hou T, Li N, Li Y, Wang W (2012) Characterization of domain-peptide interaction interface: prediction of SH3 domain-mediated protein-protein interaction network in yeast by generic structure-based models. J Proteome Res 11(5):2982–2995Gohlke H, Kiel C, Case DA (2003) Insights into protein-protein binding by binding free energy calculation and free energy decomposition for the Ras-Raf and Ras-RalGDS complexes. J Mol Biol 330(4):891–913Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA, Jr., Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09 revision D.01. Gaussian Inc, WallingfordBader RFW (1994) Atoms in molecules: a quantum theory. Clarendon, OxfordLu T, Chen F (2012) Multiwfn: a multifunctional wavefunction analyzer. J Comput Chem 33(5):580–592Case DA, Cheatham Iii TE, Darden T, Gohlke H, Luo R, Merz Jr KM, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) The amber biomolecular simulation programs. J Comput Chem 26(16):1668–1688. https://doi.org/10.1002/jcc.20290Angel Guio JE, Santiago A, Rossi R, Migliore de Angel B, Barolo S, Andujar S, Hernandez V, Rosales C, Charris JE, Suarez-Roca H, Israel A, Ramirez MM, Ortega J, Cano NH, Enriz RD (2011) Synthesis and preliminary pharmacological evaluation of methoxilated indoles with possible dopaminergic central action. Lat Am J Pharm 30(10):1934Andujar SA, Tosso RD, Suvire FD, Angelina E, Peruchena N, Cabedo N, Cortes D, Enriz RD (2012) Searching the “biologically relevant” conformation of dopamine: a computational approach. J Chem Inf Model 52(1):99–112. https://doi.org/10.1021/ci2004225Sealfon SC, Chi L, Ebersole BJ, Rodic V, Zhang D, Ballesteros JA, Weinstein H (1995) Related contribution of specific helix 2 and 7 residues to conformational activation of the serotonin 5-HT2A receptor. J Biol Chem 270(28):16683–16688Trzaskowski B, Latek D, Yuan S, Ghoshdastider U, Debinski A, Filipek S (2012) Action of molecular switches in GPCRs - theoretical and experimental studies. Curr Med Chem 19(8):1090–1109. https://doi.org/10.2174/092986712799320556Tosso RD, Andujar SA, Gutierrez L, Angelina E, Rodriguez R, Nogueras M, Baldoni H, Suvire FD, Cobo J, Enriz RD (2013) Molecular modeling study of dihydrofolate reductase inhibitors. Molecular dynamics simulations, quantum mechanical calculations, and experimental corroboration. J Chem Inf Model 53(8):2018–2032Ortiz JE, Pigni NB, Andujar SA, Roitman G, Suvire FD, Enriz RD, Tapia A, Bastida J, Feresin GE (2016) Alkaloids from Hippeastrum Argentinum and their cholinesterase-inhibitory activities: an in vitro and in Silico study. J Nat Prod 79(5):1241–1248. https://doi.org/10.1021/acs.jnatprod.5b00785Luchi AM, Angelina EL, Andujar SA, Enriz RD, Peruchena NM (2016) Halogen bonding in biological context: a computational study of D2 dopamine receptor. J Phys Org Chem 29 (11):645-655. https://doi.org/10.1002/poc.358

30-Day morbidity and mortality of bariatric metabolic surgery in adolescence during the COVID-19 pandemic – The GENEVA study

Background: Metabolic and bariatric surgery (MBS) is an effective treatment for adolescents with severe obesity. Objectives: This study examined the safety of MBS in adolescents during the coronavirus disease 2019 (COVID-19) pandemic. Methods: This was a global, multicentre and observational cohort study of MBS performed between May 01, 2020, and October 10,2020, in 68 centres from 24 countries. Data collection included in-hospital and 30-day COVID-19 and surgery-specific morbidity/mortality. Results: One hundred and seventy adolescent patients (mean age: 17.75 ± 1.30 years), mostly females (n = 122, 71.8%), underwent MBS during the study period. The mean pre-operative weight and body mass index were 122.16 ± 15.92 kg and 43.7 ± 7.11 kg/m2, respectively. Although majority of patients had pre-operative testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (n = 146; 85.9%), only 42.4% (n = 72) of the patients were asked to self-isolate pre-operatively. Two patients developed symptomatic SARS-CoV-2 infection post-operatively (1.2%). The overall complication rate was 5.3% (n = 9). There was no mortality in this cohort. Conclusions: MBS in adolescents with obesity is safe during the COVID-19 pandemic when performed within the context of local precautionary procedures (such as pre-operative testing). The 30-day morbidity rates were similar to those reported pre-pandemic. These data will help facilitate the safe re-introduction of MBS services for this group of patients

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field