Deciphering Master Gene Regulators and Associated Networks of Human Mesenchymal Stromal Cells

Mesenchymal Stromal Cells (MSC) are multipotent cells characterized by self-renewal, multilineage differentiation, and immunomodulatory properties. To obtain a gene regulatory profile of human MSCs, we generated a compendium of more than two hundred cell samples with genome-wide expression data, including a homogeneous set of 93 samples of five related primary cell types: bone marrow mesenchymal stem cells (BM-MSC), hematopoietic stem cells (HSC), lymphocytes (LYM), fibroblasts (FIB), and osteoblasts (OSTB). All these samples were integrated to generate a regulatory gene network using the algorithm ARACNe (Algorithm for the Reconstruction of Accurate Cellular Networks; based on mutual information), that finds regulons (groups of target genes regulated by transcription factors) and regulators (i.e., transcription factors, TFs). Furtherly, the algorithm VIPER (Algorithm for Virtual Inference of Protein-activity by Enriched Regulon analysis) was used to inference protein activity and to identify the most significant TF regulators, which control the expression profile of the studied cells. Applying these algorithms, a footprint of candidate master regulators of BM-MSCs was defined, including the genes EPAS1, NFE2L1, SNAI2, STAB2, TEAD1, and TULP3, that presented consistent upregulation and hypomethylation in BM-MSCs. These TFs regulate the activation of the genes in the bone marrow MSC lineage and are involved in development, morphogenesis, cell differentiation, regulation of cell adhesion, and cell structure

Bozepinib: A Promising Selective Derivative Targeting Breast Cancer Stem Cells

Bozepinib is a potent antitumour compound that shows an IC50 of 0.166 μM against MDA-MB-231 human breast cancer cell line. It is also a very selective drug that presents a therapeutic index (TI) of 11.0 against MDA-MB-231 in relation to the normal MCF-10A. It is important to identify new cancer stem-like cells (CSCs) anticancer drugs to struggle against the resistance and the high risk of relapse in patients. In the present chapter, we show how bozepinib demonstrated selectivity on cancer cells and showed an inhibitory effect over kinases involved in carcinogenesis, proliferation and angiogenesis. Bozepinib inhibits HER-2 signaling pathway and JNK and ERK kinases. In addition, it has an inhibitory effect on AKT and VEGF together with anti-angiogenic and anti-migratory activities. Interestingly, bozepinib suppresses the formation of both mammo- and colonospheres and eliminated ALDH+ CSC subpopulations at a low micromolar range similar to salinomycin. It also induces the downregulation of SOX2, c-MYC and β-CATENIN and upregulation of the GLI-3 Hedgehog signaling repressor. Finally, bozepinib shows in vivo antitumor and anti-metastatic efficacy in xenotransplanted nude mice without presenting subacute toxicity. However, further studies in cancer patients are needed to confirm the therapeutic potential of bozepinib

Problemas metodológicos en la medición del rendimiento policial de la Guardia Civil en delincuencia organizada

El crimen organizado es un fenómeno dinámico y adaptativo, lo que dificulta enormemente su represión tanto en la actuación policial como en un desarrollo jurídico adecuado, que no evoluciona a la misma rapidez que esta forma delictiva, lo cual puede conllevar en ocasiones la impunidad de sujetos implicados. Por ello, se considera conveniente estudiar el grado de ajuste que se da entre la actividad policial y la judicial. Con el objetivo de encontrar la metodología óptima para el estudio comparativo entre la actuación policial y los resultados judiciales en materia de delincuencia organizada en España, se ha propuesto la siguiente hipótesis de trabajo: existencia de un desajuste entre las sentencias judiciales condenatorias y la actuación policial desempeñada por la Guardia Civil. A partir de Informes de explotación de operaciones sobre crimen organizado de la Guardia Civil desarrolladas entre los años 2004 y 2009, y sus sentencias correspondientes, se obtiene un conjunto de variables que permiten operativizar el esfuerzo policial y los resultados judiciales, de modo que se pueden comparar entre sí. Los resultados obtenidos mediante esta investigación preliminar permiten describir el recorrido judicial completo de las operaciones analizadas; identificar los principales problemas que se dan a la hora de conseguir sentencias a partir de los informes policiales; proponer soluciones para mejorar esa búsqueda; desarrollar unos primeros índices para cuantificar la actividad policial y el resultado judicial, que permitan llegar a formular una medida del rendimiento policial, y en suma, enunciar recomendaciones para incrementar ese rendimient

Models of Sports Management in Fitness Centres. Influence of Sex, Age and Sport Frequency. Linear Models vs. Qualitative Comparative Analysis

Knowing the perceptions of users of sports services has always been an object of analysis within sports management. This paper attempts to analyse what influences the satisfaction and future intentions of fitness centre customers, beyond management variables, by using two different methodologies. A sample of 389 users of a private sports centre was used. Both linear relationships between variables and the combination of sets were analysed using fuzzy set Qualitative Comparative Analysis fsQCA. It is concluded that management variables (service quality, satisfaction and perceived value) are very important for the prediction of management models, but that, according to the interaction methodology between variables, both frequency and sociodemographic variables play an important role in achieving satisfied and loyal users of the sports service. For the prediction of customers’ future intentions, within the analysed sets, it is observed that satisfaction and perceived value are the most predictive variables (raw coverage 0.66). Therefore, and as a consequence, a high number of satisfied and loyal users of the service will allow the economic viability of this service to be achieved.Ciencias de la Actividad Física y del Deport

You must be the change you want to see in the University

Se discutirán las dos primeras misiones de la Universidad, tales como la docencia y la investigación. Además, las relaciones inter-personales son fundamentales en todo grupo humano y se abordará el papel del liderazgo en el grupo de investigación de acuerdo con las modernas tendencias del mundo empresarial. La Universidad española se encuentra en una situación excesivamente alejada de la realidad social y económica en la que vivimos. El enfoque del Espacio Europeo de Enseñanza Superior puede subsanar estas deficiencias, pero la adaptación conlleva, en mayor o menor grado, una transformación del modelo educativo actual. Lo que no está claro es que las universidades españolas hayan alcanzado o estén en vías de alcanzar plenamente la nueva configuración de la Declaración de Bolonia. Más bien están en una situación transitoria, ambigua, en la que permanecen rasgos anteriores con los nuevos. Con respecto al papel carismático del líder dentro de un grupo, merecen ser destacados aspectos tales como la motivación, delegación y resolución de conflictos, entre los muchos valores que deben adornarlo. La Universidad de Granada es una institución muy grande. El secreto para que funcione esta macro estructura es que cada uno de sus componentes, dentro de su status, se identifique con sus principios y se comprometa a cumplir con sus funciones, tanto particulares como generales. El secreto del éxito es la ilusión, trabajo y generosidad. Es así y sólo así, cuando el trabajo y la colaboración comprometida de todos sus miembros, dará lugar a una Universidad mejor.Teaching and research, two missions of the University, will be discussed herein. Moreover, the interpersonal relationships are fundamental in all human groups and the role of the leadership in the research group will be tackled according to the modern tendencies of the business world. The Spanish University has been too distanced from the social and economical reality. The approach of the European higher education system may overcome all these shortcomings, but the adaptation may lead, to a greater or a lesser degree, to a transformation of the present education system. It is not clear that the Spanish universities have reached or are now being fully reaching the new configuration of the Bologna Declaration. They are rather in a temporary ambiguous situation, in which some previous features remain with the new ones. In relation to the charismatic role of the leader within a group, aspects such as motivation, delegation of functions and resolution of conflicts warrant the greatest attention among the many values that must enhance it. The University of Granada is a vast institution. The secret for this macro-structure to work is that its components, each within its own status, be identified with its principles and be committed to observing its functions, both particular and general. The secret of the success is illusion, work and generosity. Only thus, when work and collaboration implicating all its members is a better University possible

Deciphering Master Gene Regulators and Associated Networks of Human Mesenchymal Stromal Cells.

Mesenchymal Stromal Cells (MSC) are multipotent cells characterized by self-renewal, multilineage differentiation, and immunomodulatory properties. To obtain a gene regulatory profile of human MSCs, we generated a compendium of more than two hundred cell samples with genome-wide expression data, including a homogeneous set of 93 samples of five related primary cell types: bone marrow mesenchymal stem cells (BM-MSC), hematopoietic stem cells (HSC), lymphocytes (LYM), fibroblasts (FIB), and osteoblasts (OSTB). All these samples were integrated to generate a regulatory gene network using the algorithm ARACNe (Algorithm for the Reconstruction of Accurate Cellular Networks; based on mutual information), that finds regulons (groups of target genes regulated by transcription factors) and regulators (i.e., transcription factors, TFs). Furtherly, the algorithm VIPER (Algorithm for Virtual Inference of Protein-activity by Enriched Regulon analysis) was used to inference protein activity and to identify the most significant TF regulators, which control the expression profile of the studied cells. Applying these algorithms, a footprint of candidate master regulators of BM-MSCs was defined, including the genes EPAS1, NFE2L1, SNAI2, STAB2, TEAD1, and TULP3, that presented consistent upregulation and hypomethylation in BM-MSCs. These TFs regulate the activation of the genes in the bone marrow MSC lineage and are involved in development, morphogenesis, cell differentiation, regulation of cell adhesion, and cell structure

1-(Benzenesulfonyl)-1,5-dihydro-4,1-benzoxazepine as a new scaffold for the design of antitumor compounds

Aim: Bozepinib is a potent and selective anticancer compound which chemical structure is made up of a benzofused seven-membered ring and a purine moiety. We previously demonstrated that the purine fragment does not exert antiproliferative effect per se. Methodology: A series of 1-(benzenesulfonyl)-4,1-benzoxazepine derivatives were synthesized in order to study the influence of the benzofused seven-membered ring in the biological activity of bozepinib by means of antiproliferative, cell cycle and apoptosis studies. Results & conclusion: Our results show that the methyleneoxy enamine sulfonyl function is essential in the antitumor activity of the structures and thus, it is a scaffold suitable for further modification with a view to obtain more potent antitumor compounds

Effects of dietary vegetable oil mixtures including soybean oil on intestinal oxidative stress in gilthead sea bream (Sparus aurata)

Fish oil is commonly replaced by vegetable oils in sea bream diets, but little is known about their effects on intestinal health regarding oxidative stress biomarkers. The negative effects of lipid peroxidation on digestive mucosa could have consequences in animal nutrition and welfare. In this study, five isonitrogenous (46%) and isolipidic (22%) diets with 75% of vegetable oils inclusion were evaluated: soybean oil (S) alone or different mixtures containing soybean oil with linseed (SL), linseed and rapeseed (SLR), linseed and palm (SLP), and linseed, rapeseed, and palm (SLRP). Gilthead sea bream juveniles were fed twice a day for 18 weeks. Pyloric caeca and proximal intestine samples were collected 24 h post feeding for lipid peroxidation (LPO), antioxidant enzyme activities (SOD, CAT, GPx, GST, and GR) and gene expression analyses. Pyloric caeca presented larger unhealthy changes in oxidative status than proximal intestine. Although SL-fed fish showed the highest antioxidant activities, they were unable to cope with LPO that in pyloric caeca was 31.4 times higher than in the other groups. Instead, SLP fish presented the best oxidative status, with low LPO levels, antioxidant enzyme activities, and gene expression. In summary, between the vegetable oils dietary mixtures tested, SPL would maintain better intestinal health