Distribución Geográfica de Culicidae de Argentina

Fil: Stein, Marina. Área de Entomología. Instituto de Medicina Regional. Universidad Nacional del Nordeste. Resistencia. Chaco; ArgentinaFil: Rossi, Gustavo Carlos. Centro de Estudios en Parasitología y Vectores (CEPAVE). Facultad de Ciencias Naturales y Museo. Universidad Nacional de La Plata; ArgentinaFil: Almirón, Walter R.. Instituto de Investigaciones Biológicas y Tecnológicas (IIByT). Universidad Nacional de Córdoba; Argentin

Molecular characterization of ebselen binding activity to SARS-CoV-2 main protease

There is an urgent need to repurpose drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Recent computational-experimental screenings have identified several existing drugs that could serve as effective inhibitors of the virus? main protease, Mpro, which is involved in gene expression and replication. Among these, ebselen (2-phenyl-1,2-benzoselenazol-3-one) appears to be particularly promising. Here, we examine, at a molecular level, the potential of ebselen to decrease Mpro activity. We find that it exhibits a distinct affinity for the catalytic region. Our results reveal a higher-affinity, previously unknown binding site localized between the II and III domains of the protein. A detailed strain analysis indicates that, on such a site, ebselen exerts a pronounced allosteric effect that regulates catalytic site access through surface-loop interactions, thereby inducing a reconfiguration of water hotspots. Together, these findings highlight the promise of ebselen as a repurposed drug against SARS-CoV-2.Fil: Menéndez, Cintia Anabella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Byléhn, Fabian. University of Chicago; Estados UnidosFil: Perez Lemus, Gustavo R.. University of Chicago; Estados UnidosFil: Alvarado, Walter. University of Chicago; Estados UnidosFil: de Pablo, Juan J.. University of Chicago; Estados Unido

Modeling the Binding Mechanism of Remdesivir, Favilavir, and Ribavirin to SARS-CoV-2 RNA-Dependent RNA Polymerase

Recent efforts to repurpose drugs to combat COVID-19 have identified Remdesivir as a candidate. It acts on the RNA-dependent, RNA polymerase (RdRp) of the SARS-CoV-2 virus, a protein complex responsible for mediating replication of the virus's genome. However, its exact action mechanism, and that of other nucleotide analogue inhibitors, is not known. In this study, we examine at the molecular level the interaction of this drug and that of similar nucleotide analogue inhibitors, ribavirin and favilavir, by relying on atomistic molecular simulations and advanced sampling. By analyzing the binding free energies of these different drugs, it is found that all of them bind strongly at the active site. Surprisingly, however, ribavirin and favilavir do not bind the nucleotide on the complementary strand as effectively and seem to act by a different mechanism than remdesivir. Remdesivir exhibits similar binding interactions to the natural base adenine. Moreover, by analyzing remdesivir at downstream positions of the RNA, we also find that, consistent with a "delayed"termination mechanism, additional nucleotides can be incorporated after remdesivir is added, and its highly polar 1′-cyano group induces a set of conformational changes that can affect the normal RdRp complex function. By analyzing the fluctuations of residues that are altered by remdesivir binding, and comparing them to those induced by lethal point mutations, we find a possible secondary mechanism in which remdesivir destabilizes the protein complex and its interactions with the RNA strands.Fil: Byléhn, Fabian. University of Chicago; Estados UnidosFil: Menéndez, Cintia Anabella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Perez Lemus, Gustavo R.. University of Chicago; Estados UnidosFil: Alvarado, Walter. University of Chicago; Estados UnidosFil: De Pablo, Juan J.. University of Chicago; Estados Unido

Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors

To date, effective therapeutic treatments that confer strong attenuation against coronaviruses (CoVs) remain elusive. Among potential drug targets, the helicase of CoVs is attractive due to its sequence conservation and indispensability. We rely on atomistic molecular dynamics simulations to explore the structural coordination and dynamics associated with the SARS-CoV-2 Nsp13 apo enzyme, as well as their complexes with natural ligands. A complex communication network is revealed among the five domains of Nsp13, which is differentially activated because of the presence of the ligands, as shown by shear strain analysis, principal components analysis, dynamical cross-correlation matrix analysis, and water transport analysis. The binding free energy and the corresponding mechanism of action are presented for three small molecules that were shown to be efficient inhibitors of the previous SARS-CoV Nsp13 enzyme. Together, our findings provide critical fresh insights for rational design of broad-spectrum antivirals against CoVs

Toward wide-spectrum antivirals against coronaviruses: Molecular characterization of SARS-CoV-2 NSP13 helicase inhibitors

To date, effective therapeutic treatments that confer strong attenuation against coronaviruses (CoVs) remain elusive. Among potential drug targets, the helicase of CoVs is attractive due to its sequence conservation and indispensability. We rely on atomistic molecular dynamics simulations to explore the structural coordination and dynamics associated with the SARS-CoV-2 Nsp13 apo enzyme, as well as their complexes with natural ligands. A complex communication network is revealed among the five domains of Nsp13, which is differentially activated because of the presence of the ligands, as shown by shear strain analysis, principal components analysis, dynamical cross-correlation matrix analysis, and water transport analysis. The binding free energy and the corresponding mechanism of action are presented for three small molecules that were shown to be efficient inhibitors of the previous SARS-CoV Nsp13 enzyme. Together, our findings provide critical fresh insights for rational design of broad-spectrum antivirals against CoVs.Fil: Perez Lemus, Gustavo R.. University of Chicago; Estados UnidosFil: Menéndez, Cintia Anabella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Alvarado, Walter. University of Chicago; Estados UnidosFil: Byléhn, Fabian. University of Chicago; Estados UnidosFil: de Pablo, Juan J.. University of Chicago; Estados Unido

South American giant short-faced bear (Arctotherium angustidens) diet: evidence from pathology, morphology, stable isotopes, and biomechanics

Fil: Soibelzon, Leopoldo Héctor. División Paleontología Vertebrados. Facultad de Ciencias Naturales y Museo. Universidad Nacional de La Plata; ArgentinaFil: Grinspan, Gustavo A.. Núcleo de Biomecánica. Espacio Interdisciplinario. Universidad de la República. Montevideo; UruguayFil: Bocherens, Hervé. Department of Geosciences. Biogeology. University Tübingen. Tübingen; GermanyFil: Acosta, Walter G.. Cátedra de Semiología. Facultad de Ciencias Veterinarias. Universidad Nacional de La Plata; ArgentinaFil: Jones, Washington. Núcleo de Biomecánica. Espacio Interdisciplinario. Universidad de la República. Montevideo; UruguayFil: Blanco, Ernesto R.. nstituto de Física. Facultad de Ciencias. Universidad de la República. Montevideo; UruguayFil: Prevosti, Francisco. División Mastozoología. Museo Argentino de Ciencias Naturales Bernardino Rivadavia. Buenos Aires; Argentin

Comparación de los perfiles farmacodinámicos de tres moléculas de remifentanilo en cuanto a su respuesta hemodinámica a las maniobras de laringoscopia e intubación traqueal

ResumenIntroducciónEn Colombia se comercializan diferentes moléculas de remifentanilo que nunca han sido comparadas en un entorno clínico.ObjetivoEl objetivo de este estudio fue investigar el perfil farmacodinámico de la molécula innovadora de remifentanilo (grupo O: Glaxo SmithKline Manufacturing S.P.A.) y 2 moléculas genéricas (grupo A: Laboratorios Chalver de Colombia S.A. y grupo B: Instituto Biológico Contemporáneo, Argentina) registradas en Colombia.MétodosSe llevó a cabo un experimento clínico doble ciego, aleatorizado, controlado. Se comparó la molécula original de remifentanilo (grupo O, n=29) frente a las 2 moléculas genéricas (grupo A, n=29; grupo B, n=32) durante la inducción anestésica e intubación orotraqueal de pacientes adultos ASAI sin predictores de vía aérea difícil. Se evaluaron las dosis 6, 8 y 10ng/ml (TCI, Target Controlled Infusion) con el modelo de Minto. La inducción se complementó con propofol 5μg/ml (TCI) con modelo de Schneider y rocuronio 0,6mg/kg. El desenlace primario se evaluó como las diferencias en la presión arterial media y en la frecuencia cardiaca preintubación (momento en que se alcanza la concentración objetivo en sitio efecto) y postintubación (máximo valor alcanzado en 5min).ResultadosSe observó similitud en el perfil farmacodinámico de las moléculas de remifentanilo estudiadas. Las diferencias en el cambio de frecuencia cardiaca fue de 1,27 (IC95%: –3,11;5,67) con la molécula A y 1,40 (IC95%: –2,65;5,46) con la molécula B frente a la molécula O (latidos/min). Las diferencias en el cambio de presión arterial media fueron de 1 (IC95%: –4,81;6,81) para la molécula A y de 1,82 (IC95%: –4,08;7,74) para la molécula B frente a la molécula O (mmHg). Hubo un caso de hipotensión arterial en cada grupo.ConclusiónLos resultados sugieren que desde un punto de vista farmacodinámico las moléculas innovadora y genéricas de remifentanilo son similares para la laringoscopia/intubación con dosis TCI de 6, 8 y 10ng/ml.AbstractIntroductionSeveral remifentanil products are commercialized in Colombia while these have never been compared in a clinical setting.ObjectiveThe aim of this study was to investigate the pharmacodynamic profile of the branded molecule of remifentanil (group O: Glaxo SmithKline Manufacturing S.P.A.) and two unbranded molecules (group A: Laboratorios Chalver de Colombia S.A. and group B: Instituto Biológico Contemporaneo, Argentina) registered in Colombia.MethodsWe carried out a double-blind, randomized, controlled trial. The branded molecule of remifentanil (group O, n=29) was compared with the two unbranded molecules (group A, n=29; group B, n=32) during anesthetic induction and tracheal intubation in adult patients ASAI without predictors for difficult airway. The target controlled infusion (TCI) doses evaluated were 6, 8 and 10ng/ml with the Minto model. Induction was complemented with propofol 5mcg/ml (TCI) with the Schneider model and rocuronium 0.6mg/kg. The primary outcome was defined as the difference in mean arterial pressure and heart rate pre-intubation (TCI equilibrium) and post-intubation (maximum measurement within 5minutes).ResultsA similar pharmacodinamic profile was observed between the studied remifentanil molecules. The differences in the change in heart rate were 1.27 (95% CI: –3.11;5.67) with molecule A and 1.40 (95%CI: –2.65;5.46) with molecule B against molecule O (beats/minute). The differences in the change in mean arterial pressure were 1 (95%CI: –4.81;6.81) for molecule A and 1.82 (95%CI: –4.08;7.74) for molecule B against molecule O (mmHg). There was a case of arterial hypotension in each group.ConclusionThe results suggest that from a pharmacodynamic point of view branded and unbranded remifentanil molecules are similar for laryngoscopy/intubation with TCI doses 6, 8 and 10ng/ml

Estudio Algoritmos en Computación Paralela para Herramientas de Diseño Electrónico

En el marco de desarrollo de herramientas de diseño electrónico, para sistemas de diseño de ciruitos integrados (ASICs), se hace necesaria la resolución de sistemas de ecuaciones lineales, tanto más grandes cuanto más complejidad tenga el circuito a diseñar. La ejecución de aplicaciones en forma paralela en varias computadoras aparece como una solución efectiva para conseguir la potencia de cálculo necesaria . En este artículo se presenta una estrategia de paralelización de clusters del método de Gauss-Seidel para la solución de sistemas de ecuaciones ralas. Desde el punto de vista de la solución numérica para matrices de coeficientes con poca densidad de elementos no nulos, se siguen los lineamientos estándares, es decir, esquemas de almacenamientos especiales (solamente se almacenan los elementos no nulos) y métodos iterativos de búsqueda de solución por aproximaciones sucesivas. Desde el punto de vista de la paralelización del procesamiento en clusters de computadoras, se siguen dos principios básicos: distribución de carga de procesamiento aún en el caso de clusters heterogéneos y utilización de mensajes broadcast para toda comunicación de datos entre procesos. La interconexión más usual en clusters es la provista por las redes Ethernet, y por lo tanto pueden implementar los mensajes broadcast a nivel físico con sobrecarga mínima. Se presenta el análisis de rendimiento paralelo y además los resultados obtenidos en una red local de computadoras heterogénas no dedicadas. En este caso se utiliza una implementación de la biblioteca MPI (Message Pasage Interface) para la comunicación entre procesos

A distributed computation of Interpro Pfam, PROSITE and ProDom for protein annotation

Interpro is a widely used tool for protein annotation in genome sequencing projects, demanding a large amount of computation and representing a huge time-consuming step. We present a strategy to execute programs using databases Pfam, PROSITE and ProDom of Interpro in a distributed environment using a Java-based messaging system. We developed a two-layer scheduling architecture of the distributed infrastructure. Then, we made experiments and analyzed the results. Our distributed system gave much better results than Interpro Pfam, PROSITE and ProDom running in a centralized platform. This approach seems to be appropriate and promising for highly demanding computational tools used for biological applications