Identification of Aryl Polyamines Derivatives as Anti-Trypanosoma cruzi Agents Targeting Iron Superoxide Dismutase

Chagas disease (CD) is a tropical and potentially fatal infection caused by Trypanosoma cruzi. Although CD was limited to Latin America as a silent disease, CD has become widespread as a result of globalization. Currently, 6–8 million people are infected worldwide, and no effective treatment is available. Here, we identify new effective agents against T. cruzi. In short, 16 aryl polyamines were screened in vitro against different T. cruzi strains, and lead compounds were evaluated in vivo after oral administration in both the acute and chronic infections. The mode of action was also evaluated at the energetic level, and its high activity profile could be ascribed to a mitochondria-dependent bioenergetic collapse and redox stress by inhibition of the Fe-SOD enzyme. We present compound 15 as a potential compound that provides a step forward for the development of new agents to combat CD.Ministerio de Economia, Industria y Competitividad (CONSOLIDER CSD2010–00065 and CTQ2017–90852-REDC)MINECO and FEDER funds from the EU (Projects PID2019-110751RB-I00, RED2018-102331-T and Unidad de Excelencia María de Maeztu CEX2019-000919-M)Alfonso Martín Escudero Foundatio

Library of Selenocyanate and Diselenide Derivatives as In Vivo Antichagasic Compounds Targeting Trypanosoma Cruzi Mitochondrion

Chagas disease is usually caused by tropical infection with the insect-transmitted protozoan Trypanosoma cruzi. Currently, Chagas disease is a major public health concern worldwide due to globalization, and there are no treatments neither vaccines because of the long-term nature of the disease and its complex pathology. Current treatments are limited to two obsolete drugs, benznidazole and nifurtimox, which lead to serious drawbacks. Taking into account the urgent need for strict research efforts to find new therapies, here, we describe the in vitro and in vivo trypanocidal activity of a library of selected forty-eight selenocyanate and diselenide derivatives that exhibited leishmanicidal properties. The inclusion of selenium, an essential trace element, was due to the wellknown extensive pharmacological activities for selenium compounds including parasitic diseases as T. cruzi. Here we present compound 8 as a potential compound that exhibits a better profile than benznidazole both in vitro and in vivo. It shows a fast-acting behaviour that could be attributed to its mode of action: it acts in a mitochondrion-dependent manner, causing cell death by bioenergetic collapse. This finding provides a step forward for the development of a new antichagasic agent.Ministerio de Economia, Industria y Competitividad, grant number CSD2010–00065 and CTQ2017–90852-REDCConserjería de Economía, Conocimiento, Empresas y Universidad de la Junta de Andalucia, grant number A-CTS-383-UGR18Institute of Tropical Health of University of Navarre (ISTUN)Caixa FoundationRoviralta and UbesolAlfonso Martín Escudero Foundatio

Association of Candidate Gene Polymorphisms With Chronic Kidney Disease: Results of a Case-Control Analysis in the Nefrona Cohort

Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease, cardiovascular disease and premature death. Despite classical clinical risk factors for CKD and some genetic risk factors have been identified, the residual risk observed in prediction models is still high. Therefore, new risk factors need to be identified in order to better predict the risk of CKD in the population. Here, we analyzed the genetic association of 79 SNPs of proteins associated with mineral metabolism disturbances with CKD in a cohort that includes 2, 445 CKD cases and 559 controls. Genotyping was performed with matrix assisted laser desorption ionizationtime of flight mass spectrometry. We used logistic regression models considering different genetic inheritance models to assess the association of the SNPs with the prevalence of CKD, adjusting for known risk factors. Eight SNPs (rs1126616, rs35068180, rs2238135, rs1800247, rs385564, rs4236, rs2248359, and rs1564858) were associated with CKD even after adjusting by sex, age and race. A model containing five of these SNPs (rs1126616, rs35068180, rs1800247, rs4236, and rs2248359), diabetes and hypertension showed better performance than models considering only clinical risk factors, significantly increasing the area under the curve of the model without polymorphisms. Furthermore, one of the SNPs (the rs2248359) showed an interaction with hypertension, being the risk genotype affecting only hypertensive patients. We conclude that 5 SNPs related to proteins implicated in mineral metabolism disturbances (Osteopontin, osteocalcin, matrix gla protein, matrix metalloprotease 3 and 24 hydroxylase) are associated to an increased risk of suffering CKD

Association of a single nucleotide polymorphism combination pattern of the Klotho gene with non-cardiovascular death in patients with chronic kidney disease

Chronic kidney disease (CKD) is associated with an elevated risk of all-cause mortality, with cardiovascular death being extensively investigated. However, non-cardiovascular mortality represents the biggest percentage, showing an evident increase in recent years. Klotho is a gene highly expressed in the kidney, with a clear influence on lifespan. Low levels of Klotho have been linked to CKD progression and adverse outcomes. Single nucleotide polymorphisms (SNPs) of the Klotho gene have been associated with several diseases, but studies investigating the association of Klotho SNPs with noncardiovascular death in CKD populations are lacking. The main aim of this study was to assess whether 11 Klotho SNPs were associated with non-cardiovascular death in a subpopulation of the National Observatory of Atherosclerosis in Nephrology (NEFRONA) study (n ¼ 2185 CKD patients). After 48 months of follow-up, 62 cardiovascular deaths and 108 non-cardiovascular deaths were recorded. We identified a high non-cardiovascular death risk combination of SNPs corresponding to individuals carrying the most frequent allele (G) at rs562020, the rare allele (C) at rs2283368 and homozygotes for the rare allele (G) at rs2320762 (rs562020 GG/AG þ rs2283368 CC/CT þ rs2320762 GG). Among the patients with the three SNPs genotyped (n ¼ 1016), 75 (7.4%) showed this combination. Furthermore, 95 (9.3%) patients showed a low-risk combination carrying all the opposite genotypes (rs562020 AA þ rs2283368 TT þ rs2320762 GT/TT). All the other combinations [n ¼ 846 (83.3%)] were considered as normal risk. Using competing risk regression analysis, we confirmed that the proposed combinations are independently associated with a higher fhazard ratio [HR] 3.28 [confidence interval (CI) 1.51-7.12]g and lower [HR 6 × 10- (95% CI 3.3 × 10--1.1 × 10-)] risk of suffering a non-cardiovascular death in the CKD population of the NEFRONA cohort compared with patients with the normal-risk combination. Determination of three SNPs of the Klotho gene could help in the prediction of non-cardiovascular death in CKD

Medio ambiente, sociedad, ética, auditoría y educación. La Investigación Contable en UNIMINUTO Virtual y a Distancia: Contexto y Oportunidades.

En los últimos años la educación a distancia ha mostrado ser capaz de reducir la brecha de inequidad social, de capacitar personas en lugares remotos, de brindar la posibilidad a la comunidad discapacitada y de permitirle a quienes no cuentan con suficientes recursos económicos acceder a la educación superior, la presente investigación da cuenta de los aspectos clave asociados a la decisión de matricularse en el programa de Contaduría Pública en la modalidad distancia tradicional. Se realizó un análisis de las narrativas basado en los resultados de un instrumento aplicado a 150 estudiantes. Para el análisis de datos se empleó la herramienta SenseMaker®. Los resultados evidencian aspectos personales, sociales y culturales que posicionan la oferta de educación en la modalidad a distancia como la institución que permite resignificar la vida de las persona

Medio ambiente, sociedad, ética, auditoría y educación. La Investigación Contable en UNIMINUTO Virtual y a Distancia: Contexto y Oportunidades.

En los últimos años la educación a distancia ha mostrado ser capaz de reducir la brecha de inequidad social, de capacitar personas en lugares remotos, de brindar la posibilidad a la comunidad discapacitada y de permitirle a quienes no cuentan con suficientes recursos económicos acceder a la educación superior, la presente investigación da cuenta de los aspectos clave asociados a la decisión de matricularse en el programa de Contaduría Pública en la modalidad distancia tradicional. Se realizó un análisis de las narrativas basado en los resultados de un instrumento aplicado a 150 estudiantes. Para el análisis de datos se empleó la herramienta SenseMaker®. Los resultados evidencian aspectos personales, sociales y culturales que posicionan la oferta de educación en la modalidad a distancia como la institución que permite resignificar la vida de las persona

Capitulo 2. Ciencias Naturales y Ciencias Básicas, Ingeniería y Tecnología

La diseminación de la Levitación Magnética, a pesar de lo antiguo de su tecnología, ha sido limitada. Debido a sus inconvenientes prácticos de implementación, su uso es bastante restringido, comparado con otras tecnologías (SCMaglev japonés, Transrapid alemán, o productos comerciales para ocio y entretenimiento). Con el boom de las tecnologías limpias y amigables con el medio ambiente y en concordancia con los objetivos del milenio, es pertinente plantearse el objetivo de optimizar el proceso de Levitación Magnética para generar un aprovechamiento de las ventajas de esta tecnología a nivel mecánico, eléctrico, y ambiental.  Actualmente la UNAD adelanta un proyecto de investigación cuyo objetivo es generar un modelo físico matemático de levitación magnética para aplicaciones en ingeniería. De este proyecto se ha derivado una primera revisión sistemática de los principios físicos y los modelos vigentes en Levitación Magnética

ExoClock Project. III. 450 New Exoplanet Ephemerides from Ground and Space Observations

The ExoClock project has been created to increase the efficiency of the Ariel mission. It will achieve this by continuously monitoring and updating the ephemerides of Ariel candidates, in order to produce a consistent catalog of reliable and precise ephemerides. This work presents a homogenous catalog of updated ephemerides for 450 planets, generated by the integration of ∼18,000 data points from multiple sources. These sources include observations from ground-based telescopes (the ExoClock network and the Exoplanet Transit Database), midtime values from the literature, and light curves from space telescopes (Kepler, K2, and TESS). With all the above, we manage to collect observations for half of the postdiscovery years (median), with data that have a median uncertainty less than 1 minute. In comparison with the literature, the ephemerides generated by the project are more precise and less biased. More than 40% of the initial literature ephemerides had to be updated to reach the goals of the project, as they were either of low precision or drifting. Moreover, the integrated approach of the project enables both the monitoring of the majority of the Ariel candidates (95%), and also the identification of missing data. These results highlight the need for continuous monitoring to increase the observing coverage of the candidate planets. Finally, the extended observing coverage of planets allows us to detect trends (transit-timing variations) for a sample of 19 planets. All the products, data, and codes used in this work are open and accessible to the wider scientific community

Library of Selenocyanate and Diselenide Derivatives as In Vivo Antichagasic Compounds Targeting Trypanosoma cruzi Mitochondrion.

Chagas disease is usually caused by tropical infection with the insect-transmitted protozoan Trypanosoma cruzi. Currently, Chagas disease is a major public health concern worldwide due to globalization, and there are no treatments neither vaccines because of the long-term nature of the disease and its complex pathology. Current treatments are limited to two obsolete drugs, benznidazole and nifurtimox, which lead to serious drawbacks. Taking into account the urgent need for strict research efforts to find new therapies, here, we describe the in vitro and in vivo trypanocidal activity of a library of selected forty-eight selenocyanate and diselenide derivatives that exhibited leishmanicidal properties. The inclusion of selenium, an essential trace element, was due to the well-known extensive pharmacological activities for selenium compounds including parasitic diseases as T. cruzi. Here we present compound 8 as a potential compound that exhibits a better profile than benznidazole both in vitro and in vivo. It shows a fast-acting behaviour that could be attributed to its mode of action: it acts in a mitochondrion-dependent manner, causing cell death by bioenergetic collapse. This finding provides a step forward for the development of a new antichagasic agent

Library of Selenocyanate and Diselenide Derivatives as In Vivo Antichagasic Compounds Targeting Trypanosoma cruzi Mitochondrion

Chagas disease is usually caused by tropical infection with the insect-transmitted protozoan Trypanosoma cruzi. Currently, Chagas disease is a major public health concern worldwide due to globalization, and there are no treatments neither vaccines because of the long-term nature of the disease and its complex pathology. Current treatments are limited to two obsolete drugs, benznidazole and nifurtimox, which lead to serious drawbacks. Taking into account the urgent need for strict research efforts to find new therapies, here, we describe the in vitro and in vivo trypanocidal activity of a library of selected forty-eight selenocyanate and diselenide derivatives that exhibited leishmanicidal properties. The inclusion of selenium, an essential trace element, was due to the well-known extensive pharmacological activities for selenium compounds including parasitic diseases as T. cruzi. Here we present compound 8 as a potential compound that exhibits a better profile than benznidazole both in vitro and in vivo. It shows a fast-acting behaviour that could be attributed to its mode of action: it acts in a mitochondrion-dependent manner, causing cell death by bioenergetic collapse. This finding provides a step forward for the development of a new antichagasic agent