Analysis of the role of Granzyme-A in the development of colorectal cancer stem cells

Colorectal cancer is the third leading cause of cancer death worldwide with nearly 150.000 new cases diagnose annually. New therapies have been developed for the last years targeting different proliferation and survival signalling pathways but few advances have been done to avoid relapse in patients. Cancer stem cells are proposed as the main mechanism of resistance in current therapies. These cells have been described as a subset among all the tumour cell populations which have stemness properties such as self-renewal and differentiation capabilities. These features allow them to survive after antitumour treatments and regenerate the entire tumour mass. Also, cancer stem cells have been proposed as the responsible of metastasis. Inflammation in colorectal cancer is a sign of poor prognosis and it has been proposed as the main driver of the tumour progression. Its relation with cancer stem cells has not been clasified yet but pro-inflammatory molecules such as TNF-α or IL-1B are able to activate cancer stem cells-related signalling pathways such as Wnt or Notch pathways. Granzyme-A, a protease released by immune cells, is involved in implication during like bacterial sepsis or arthritis. Our preliminary data indicate it is involved in development of colorectal cancer. The current study analyse the implication of Granzyme-A in the activation of CSCs during inflammation-associated colorectal cancer in a mouse model

Caracterización biológica de una nueva serie de compuestos químicos con actividad antimicrobiana

Antimicrobial resistance has become a serious global health problem, not only because resistant bacteria cause millions of deaths worldwide, but also because fewer antibiotics are approved to treat these infections. Currently, there is a great need to find new antimicrobial agents effective against multi-drug resistant strains. In this project, we have characterized the antimicrobial activity of a library containing 47 chemical compounds with related structural features never tested before in biological processes. To this aim, a screening strategy was followed to select those compounds showing in vitro activity and without cytotoxicity. First, a single concentration assay (single shot) was performed against 17 bacterial strains, including Gram-positives, Gram-negatives, and mycobacteria. Thirteen compounds were selected with activity at 50 μM against at least one of the strains. Second, dose-response and time-kill kinetics assays were also performed, selecting 5 compounds with bactericidal activity against Gram-positive bacteria at concentrations ranging from 0.78 to 50 μM. Third, cytotoxicity assays in human hepatic cells were performed to determine selectivity indexes (S.I); these ranged from 3.4 to 70.5. Fourth, concentrations of 5 μM were found not mutagenic by the Ames’ Test. Finally, structure-activity relationship (SAR) studies defined chemical structural features determining the compounds’ antimicrobial activity. In summary, we have identified active compounds against Gram-positive bacteria with good S.I., which opens a new research line with the potential to develop new antimicrobial agents. Future assays may include more detailed studies of in vitro and in vivo activity, toxicity, determination of the molecular mechanism of action and medicinal chemistry efforts in order to optimize these series of compounds

Characterization of the catalytic flexible loop in the dihydroorotase domain of the human multi-enzymatic protein CAD

The dihydroorotase (DHOase) domain of the multifunctional protein carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD) catalyzes the third step in the de novo biosynthesis of pyrimidine nucleotides in animals. The crystal structure of the DHOase domain of human CAD (huDHOase) revealed that, despite evolutionary divergence, its active site components are highly conserved with those in bacterial DHOases, encoded as monofunctional enzymes. An important element for catalysis, conserved from Escherichia coli to humans, is a flexible loop that closes as a lid over the active site. Here, we combined mutagenic, structural, biochemical, and molecular dynamics analyses to characterize the function of the flexible loop in the activity of CAD's DHOase domain. A huDHOase chimera bearing the E. coli DHOase flexible loop was inactive, suggesting the presence of distinctive elements in the flexible loop of huDHOase that cannot be replaced by the bacterial sequence. We pinpointed Phe-1563, a residue absolutely conserved at the tip of the flexible loop in CAD's DHOase domain, as a critical element for the conformational equilibrium between the two catalytic states of the protein. Substitutions of Phe-1563 with Ala, Leu, or Thr prevented the closure of the flexible loop and inactivated the protein, whereas substitution with Tyr enhanced the interactions of the loop in the closed position and reduced fluctuations and the reaction rate. Our results confirm the importance of the flexible loop in CAD's DHOase domain and explain the key role of Phe-1563 in configuring the active site and in promoting substrate strain and catalysi

A PROSPECTIVE LOOK AT MUNICIPAL PUBLIC PLANNING

Consciente de que es mucho lo que podemos aportar y apostando a enrumbarnos por este camino, en este artículo informativo que tiene como propósito presentar esta temática denominada: Una Mirada Prospectiva de la Planificación Pública Municipal, análisis actual con propuestas prospectivas, sobre la planificación pública municipal en Venezuela, haciendo énfasis en el municipio Palavecino, del estado Lara, como un análisis reflexivo de crear planes y políticas públicas que surtan un efecto de suma felicidad posible, establecida en la Constitución de la República Bolivariana de Venezuela (CRBV); en este orden de ideas planteo un acicate de la investigación sobre mi experiencia de los modelos de construcción de políticas públicas usados a partir de la llamada descentralización gubernamental, tratando de llegar de forma accesible a la población, citando los desaciertos de esos modelos de planificación importados que hasta la fecha y según mi aporte no observamos el beneficio de acierto para el fin que queremos llegar. Es por esto que, como aporte integral, apostando al desarrollo institucional como gobierno cercano a las comunidades, planteo estructurar y crear una metodología de construcción de políticas públicas de una manera participativa y protagónica con las diferentes organizaciones comunitarias, religiosas, culturales, educativas entre otras. Por otra parte, relatando por toda esa ruta transitada en lo laboral, social y comunitario ahora bien me han dado las herramientas y los conocimientos utilizando los principios de la andragogía, no obstante poder brindar un aporte como investigador a nuestro Municipio por lo cual el día de mañana logremos ver ese avance en planificación y brindar grandes aportes a otras municipalidades de la nación. Es por esto que buscado la salida de este modelo burocrático que destruye el sistema de la administración pública, planteo desarrollar una reingeniería organizativa, donde estoy construyendo el camino o la ruta necesaria como aporte al proyecto país.Aware that there is much we can contribute and betting on heading down this path, in this informative article whose purpose is to present this theme called: A Prospective Look at Municipal Public Planning, current analysis with prospective proposals, on municipal public planning in Venezuela, emphasizing the municipality of Palavecino, in the state of Lara, as a reflexive analysis of creating plans and public policies that have the greatest possible happiness effect, established in the Constitution of the Bolivarian Republic of Venezuela (CRBV); In this order of ideas, I propose a research spur on my experience of the construction models of public policies used from the so-called governmental decentralization, trying to reach the population in an accessible way, citing the mistakes of those imported planning models. that to date and according to my contribution we do not observe the benefit of success for the purpose we want to achieve. That is why as an integral contribution, betting on institutional development as a government close to the communities, I propose to structure and create a methodology for the construction of public policies in a participatory and leading manner with the different community, religious, cultural, educational organizations, among others. On the other hand, recounting all that route traveled in the labor, social and community spheres, now they have given me the tools and knowledge using the principles of andragogy, despite being able to provide a contribution as a researcher to our Municipality for which the day of tomorrow we will be able to see that progress in planning and provide great contributions to other municipalities in the nation. For this reason, that I have sought the way out of this bureaucratic model that destroys the public administration system, I propose to develop an organizational reengineering, where I am building the necessary path or route as a contribution to the country project

Improving long line stability by integrating renewables using static synchronous generators

Postprint (author's final draft

Synchronous power controller merits for dynamic stability improvement in long line by renewables

Postprint (author's final draft

Ivermectin and Novel Coronavirus Disease (COVID-19): Keeping Rigor in Times of Urgency.

Ivermectin is a widely used drug for the treatment and control of several neglected tropical diseases.The drug has an excellent safety profile, with more than 2.5 billion doses distributed in the last 30 years, and its potential to reduce malaria transmission by killing mosquitoes is under evaluation in several trials around the world. Ivermectin inhibits the in vitro replication of some positive, single-stranded RNA viruses, namely, dengue virus (DNV), Zika virus, yellow fever virus, and others

Structure, Functional Characterization, and Evolution of the Dihydroorotase Domain of Human CAD

SummaryUpregulation of CAD, the multifunctional protein that initiates and controls the de novo biosynthesis of pyrimidines in animals, is essential for cell proliferation. Deciphering the architecture and functioning of CAD is of interest for its potential usage as an antitumoral target. However, there is no detailed structural information about CAD other than that it self-assembles into hexamers of ∼1.5 MDa. Here we report the crystal structure and functional characterization of the dihydroorotase domain of human CAD. Contradicting all assumptions, the structure reveals an active site enclosed by a flexible loop with two Zn2+ ions bridged by a carboxylated lysine and a third Zn coordinating a rare histidinate ion. Site-directed mutagenesis and functional assays prove the involvement of the Zn and flexible loop in catalysis. Comparison with homologous bacterial enzymes supports a reclassification of the DHOase family and provides strong evidence against current models of the architecture of CAD

Afrontamiento, vida personal y familiar de profesores que pertenecen al Sistema Nacional de Investigadores (SNI) de una universidad del sureste de México

This study aimed to know the self-perception of the dimensions of coping, as well as personal and family life of researchers belonging to the National System of Researchers (SNI) of a public university in southeastern, Mexico. It was developed from a quantitative, descriptive-exploratory perspective. The study was made up of 121 (96%) of the researchers assigned to the SNI, of which 72 (59.5%) are men (M age = 43.3, SD = 9.5 years) and 49 (40.5%) women (M age = 44.2, DE = 8.4 years). The information-gathering instrument was a questionnaire that was answered with a Likert scale, as well as three open questions. It was found that the members of the SNI of the University of the study are young, and have mostly recognition at level I. In relation to the dimensions of coping and personal and family life, the subjects are almost always satisfied with the variables associated with these dimensions. In sum, the factors that influence their permanence or admission to the SNI, are the skills they possess, the interest, the family and the preparation they received in the field of research.El presente estudio tuvo como objetivo conocer la autopercepción de las dimensiones de afrontamiento, vida personal y familiar de investigadores que pertenecen al Sistema Nacional de Investigadores (SNI) de una universidad pública del sureste de México. Se desarrolló desde una perspectiva cuantitativa, descriptiva-exploratoria. El estudio estuvo conformado por 121 (96%) de los investigadores adscritos al SNI, de los cuales 72 (59.5%) son hombres (M edad = 43.3, DE = 9.5 años) y 49 (40.5%) mujeres (M edad = 44.2, DE = 8.4 años). El instrumento de recolección de la información fue un cuestionario con escala tipo Likert, así como tres preguntas abiertas. Se encontró que los miembros del SNI de la Universidad en estudio son jóvenes y tienen mayormente reconocimiento en el nivel I. En relación a las dimensiones de afrontamiento, vida personal y familiar, los sujetos se encuentran satisfechos casi siempre con las variables asociadas a estas dimensiones. En suma, los factores que influyen en su permanencia o ingreso al SNI son las habilidades que poseen, el interés, la familia y la preparación que recibieron en el campo de la investigación

Clasificación de distintos conjuntos de datos utilizados en evaluación de métodos de extracción de conocimiento creados para la web

En varios artículos se han utilizado distintos textos de prueba, como datos de entrada para medir el desempeño de los métodos de extracción de relaciones semánticas para la Web (OIE): ReVerb y ClausIE. Sin embargo estos textos nunca han sido analizados para entender si ellos guardan o no similitudes o para saber si existe entre ellos un lenguaje común o pertenecen a un mismo dominio. Es la intención de este trabajo analizar dichos textos utilizando distintos algoritmos de clasificación. Y comprender si se pueden agrupar de una forma coherente, de tal suerte que a priori uno pueda identificar que textos son los que trabajan mejor con ClausIE y cuales con ReVerb.XIII Workshop Bases de datos y Minería de Datos (WBDMD).Red de Universidades con Carreras en Informática (RedUNCI