Modeling of leishmaniasis infection dynamics: novel application to the design of effective therapies

<p>Abstract</p> <p>Background</p> <p>The WHO considers leishmaniasis as one of the six most important tropical diseases worldwide. It is caused by parasites of the genus <it>Leishmania </it>that are passed on to humans and animals by the phlebotomine sandfly. Despite all of the research, there is still a lack of understanding on the metabolism of the parasite and the progression of the disease. In this study, a mathematical model of disease progression was developed based on experimental data of clinical symptoms, immunological responses, and parasite load for <it>Leishmania amazonensis </it>in <it>BALB/c </it>mice.</p> <p>Results</p> <p>Four biologically significant variables were chosen to develop a differential equation model based on the GMA power-law formalism. Parameters were determined to minimize error in the model dynamics and time series experimental data. Subsequently, the model robustness was tested and the model predictions were verified by comparing them with experimental observations made in different experimental conditions. The model obtained helps to quantify relationships between the selected variables, leads to a better understanding of disease progression, and aids in the identification of crucial points for introducing therapeutic methods.</p> <p>Conclusions</p> <p>Our model can be used to identify the biological factors that must be changed to minimize parasite load in the host body, and contributes to the design of effective therapies.</p

Identification of 1,2,3-triazolium salt-based inhibitors of Leishmania infantum trypanothione disulfide reductase with enhanced antileishmanial potency in cellulo and increased selectivity

N-methylation of the triazole moiety present in our recently described triazole-phenyl-thiazole dimerization disruptors of Leishmania infantum trypanothione disulfide reductase (LiTryR) led to a new class of potent in- hibitors that target different binding sites on this enzyme. Subtle structural changes among representative library members modified their mechanism of action, switching from models of classical competitive inhibition to time- dependent mixed noncompetitive inhibition. X-ray crystallography and molecular modeling results provided a rationale for this distinct behavior. The remarkable potency and selectivity improvements, particularly against intracellular amastigotes, of the LiTryR dimerization disruptors 4c and 4d reveal that they could be exploited as leishmanicidal agents. Of note, L. infantum promastigotes treated with 4c significantly reduced their low- molecular-weight thiol content, thus providing additional evidence that LiTryR is the main target of this novel compound.This work has been financially supported by the Spanish MICINN (Projects PID2019-104070RB-C21, PID2019-104070RB-C22 and PID2020-115331 GB-I00), the Spanish Agencia Estatal Consejo Superior de Investigaciones Científicas (CSIC, Projects CSIC-PIE-201980E100 and CSIC-PIE-201980E028), and the Comunidad de Madrid (PLATESA2-CM ref. S-2018/BAA-4370). The Spanish MEC is also acknowledged for FPU grants to A. R. and to J.C.G. P.A.S.M. thanks to the Division of Physio- logical Chemistry and the Otto-Loewi Research Center of the Medical University of Graz for their support with the scienfic cluster where the calculations contained in this work were run. We thank Ricardo Lau- reano-Rodríguez, Juan Antonio Rodríguez-Gutierrez, and Laura Lagar- tera for technical assistance with SPR experiments.Peer reviewe

Development of Proteomics-Based Fungicides: New Strategies for Environmentally Friendly Control of Fungal Plant Diseases

Proteomics has become one of the most relevant high-throughput technologies. Several approaches have been used for studying, for example, tumor development, biomarker discovery, or microbiology. In this “post-genomic” era, the relevance of these studies has been highlighted as the phenotypes determined by the proteins and not by the genotypes encoding them that is responsible for the final phenotypes. One of the most interesting outcomes of these technologies is the design of new drugs, due to the discovery of new disease factors that may be candidates for new therapeutic targets. To our knowledge, no commercial fungicides have been developed from targeted molecular research, this review will shed some light on future prospects. We will summarize previous research efforts and discuss future innovations, focused on the fight against one of the main agents causing a devastating crops disease, fungal phytopathogens

Estudio de comunidades de matorral mediterráneo I

Conjunto de guiones de prácticas de Ecología, correspondientes al bloque temático sobre el estudio de comunidades, y material complementario (estadillo y plantilla para la matriz de datos)

Guía Rápida de SPSS v.25 (Prácticas de Ecología)

Guía rápida de SPSS v.25 para usar en las Prácticas de Ecología (Grado en Biología, 3er curso

A taxonomy of best-reply multifunctions in 2×2×2 trimatrix games

Non-cooperative games, Best-reply multifunction, Nash equilibrium, 91A06, 91A05,

Tromboembolismo pulmonar : proceso asistencial integrado

publicado en la página web de la Consejería de Igualdad, Salud y Políticas Sociales: www.juntadeandalucia.es/salud (Consejería de Igualdad, Salud y Políticas Sociales / Profesionales / Nuestro Compromiso por la Calidad / Procesos Asistenciales Integrados)YesProceso seleccionado por su incidencia y elevada morbimortalidad, siendo la tercera causa de fallecimiento por patología cardiovascular. Constituye la primera causa de muerte evitable intrahospitalaria. Una identificación diagnóstica precisa seguida de un tratamiento anticoagulante adecuado puede reducir la mortalidad del 30% al 2-8%