Síntesis, Caracterización y Estudio en Disolución del Ácido N-2-(4-amino-1,6-dihidro-1-metil-5-nitroso-6-oxopirimidinil)- L-Glutámico

Se ha sintetizado el ácido N-2-(4-amino-1,6-dihidro-1-metil-5-nitroso-6- oxopirimidinil)-L-glutámico (AMNGLUH3) y caracterizado mediante técnicas de análisis elemental y térmico, espectroscópicas de ir, uv-visible y RMN de 1H, 13C, y 15N. Se ha estudiado el comportamiento ácido-base en disolución acuosa mediante técnicas potenciométricas y experimentos de RMN de 1H y 13C. El trianión AMNGLU3- experimenta cuatro procesos sucesivos de protonación que corresponden al átomo de nitrógeno y grupos carboxilato del resto aminoacídico y al grupo nitroso del anillo pirimidínico

Long-term priming of hypothalamic microglia is associated with energy balance disturbances under diet-induced obesity

Exposure of microglia to an inflammatory environment may lead to their priming and exacerbated response to future inflammatory stimuli. Here we aimed to explore hypothalamic microglia priming and its consequences on energy balance regulation. A model of intracerebroventricular administration of neuraminidase (NA, which is present in various pathogens such as influenza virus) was used to induce acute neuroinflammation. Evidences of primed microglia were observed 3 months after NA injection, namely (1) a heightened response of microglia located in the hypothalamic arcuate nucleus after an in vivo inflammatory challenge (high fat diet [HFD] feeding for 10 days), and (2) an enhanced response of microglia isolated from NA-treated mice and challenged in vitro to LPS. On the other hand, the consequences of a previous NA-induced neuroinflammation were further evaluated in an alternative inflammatory and hypercaloric scenario, such as the obesity generated by continued HDF feeding. Compared with sham-injected mice, NA-treated mice showed increased food intake and, surprisingly, reduced body weight. Besides, NA-treated mice had enhanced microgliosis (evidenced by increased number and reactive morphology of microglia) and a reduced population of POMC neurons in the basal hypothalamus. Thus, a single acute neuroinflammatory event may elicit a sustained state of priming in microglial cells, and in particular those located in the hypothalamus, with consequences in hypothalamic cytoarchitecture and its regulatory function upon nutritional challenges.Ministerio de Economía, Industria yCompetitividad, Gobierno de España, Grant/Award Number: SAF2017-83645; Ministeriode Educación y Formación Profesional; Funding for open access charge: Universidadde Málaga/CBU

Partial inhibition of CSF1R signaling reverses long-term microglial priming.

Microglial cells are main actors in acute neuroinflammation, during which they activate to later return to a basal resting state. Sometimes they retain immune memory of previous neuroinflammatory events, turning into primed microglia, which develop exacerbated responses to new stimuli. Brain can be depleted of microglia by treatment with the CSF1R inhibitor PLX5622. Treatment termination allows for microglia regeneration, new cells presenting a resting state. Here we aimed to explore if treatment with lower doses of PLX5622 can reverse microglial priming. We induced microglial priming in mice by provoking acute neuroinflammation by icv administration of neuraminidase. After 3 weeks, when neuroinflammation is largely solved, mice were treated with a daily dose of PLX5622 for 12 days. Then, microglial repopulation was allowed for 7 weeks. Finally, a second stimulus was applied (ip LPS) to induce inflammatory activation of primed microglia, and animals were sacrificed 12 hours later. Brains were collected to analyze microglial cell number and activation by morphological analysis, and expression level of key genes by qPCR; these parameters were evaluated in two regions: the periventricular area of the hypothalamus and the hippocampus. In hypothalamic paraventricular nucleus the number of microglial cells was the same regardless the treatment; however, it was slightly reduced in the dentate gyrus of the hippocampus of PLX5622 treated mice. Morphological analysis of microglial cells was carried out by fractal, sholl and skeleton analysis. All of them pointed that microglia sampled from NA injected mice had a more activated profile (less ramified cells), which was reversed by PLX5622 treatment. Besides, expression of pro-inflammatory related genes (IL1β, IL6, TNFα, NLRP3, TLR4) pointed to the same direction. Thus, our results suggest that PLX5622 used at low doses reverses microglial priming, while does not fully deplete microglial population.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

MYC as therapeutic target in leukemia and lymphoma

MYC is a transcription factor that is involved in the expression of many genes. Deregulated MYC is found in about half of human tumors, being more prevalent in hematological neoplasms. Deregulation mechanisms include chromosomal translocation (particularly in lymphoma), amplification, and hyperactivation of MYC transcription. Here we review MYC involvement in the major types of leukemia and lymphoma. MYC rearrangements appear in all Burkitt lymphomas and are common in other lymphoma types, whereas in acute lymphoblastic leukemia, acute myeloid leukemia, lymphoproliferative, and myeloproferative diseases, they are less frequent. However, MYC overexpression is present in all types of hematological malignancies and often correlates with a worse prognosis. Data in leukemia-derived cells and in animal models of lymphomagenesis and leukemogenesis suggest that MYC would be a good therapeutic target. Several MYC-directed therapies have been assayed in preclinical settings and even in clinical trials. First, peptides and small molecules that interrupt the MYC–MAX interaction impair MYC-mediated tumorogenesis in several mouse models of solid tumors, although not yet in lymphoma and leukemia models. Second, there are a number of small molecules inhibiting the interaction of MYC–MAX heterodimers with DNA, still in the preclinical research phase. Third, inhibitors of MYC expression via the inhibition of BRD4 (a reader of acetylated histones) have been shown to control the growth of MYC-transformed leukemia and lymphoma cells and are being used in clinic trials. Finally, we review a number of promising MYC-mediated synthetic lethal approaches that are under study and have been tested in hematopoietic neoplasms

Spread of a New Parasitic B Chromosome Variant Is Facilitated by High Gene Flow

The B24 chromosome variant emerged several decades ago in a Spanish population of the grasshopper Eyprepocnemis plorans and is currently reaching adjacent populations. Here we report, for the first time, how a parasitic B chromosome (a strictly vertically transmitted parasite) expands its geographical range aided by high gene flow in the host species. For six years we analyzed B frequency in several populations to the east and west of the original population and found extensive spatial variation, but only a slight temporal trend. The highest B24 frequency was found in its original population (Torrox) and it decreased closer to both the eastern and the western populations. The analysis of Inter Simple Sequence Repeat (ISSR) markers showed the existence of a low but significant degree of population subdivision, as well as significant isolation by distance (IBD). Pairwise Nem estimates suggested the existence of high gene flow between the four populations located in the Torrox area, with higher values towards the east. No significant barriers to gene flow were found among these four populations, and we conclude that high gene flow is facilitating B24 diffusion both eastward and westward, with minor role for B24 drive due to the arrival of drive suppressor genes which are also frequent in the donor population.This study was supported by a grant from the Spanish Ministerio de Ciencia e Innovación (CGL2009-11917), and was partially performed by FEDER ("Fondo Europeo de Desarrollo" - European Regional Development Fund - ERDF) funds. MIMP was supported by a fellowship (FPU) from the Spanish Ministerio de Ciencia e Innovación

Primed microglia after acute neuroinflammation may drive an enhanced stress response.

Microglial cells become activated during acute neuroinflammation and usually they return to their basal surveillant state in a few days. However, sometimes microglia evolve towards a primed state characterized by an exacerbated response to new stimuli, which may jeopardize brain functions. Here we aimed to explore microglial priming in the hypothalamus and its consequences on the neuroendocrine regulation of the stress response. To induce priming we used a model of acute ventricular neuroinflammation by intracerebroventricular (ICV) injection of the enzyme neuraminidase (NA). Three months later, an acute stressor (consisting in forced swimming) was applied to investigate the activation of the hypothalamic-pituitary-adrenal axis and the stress response elicited, as well as the inflammatory activation of hypothalamic microglial cells. Stressed rats previously injected with NA had increased plasma levels of corticosterone compared to control rats that were equally stressed but had been ICV injected with saline. Also, qPCR studies revealed that NA-treated rats presented an increased expression of the microglial marker IBA1 and of the inflammasome protein NLRP3. Concomitantly, the morphological analysis of hypothalamic microglial cells showed a morphological bias towards a slightly activated state in microglia of NA injected rats compared to those of saline injected controls. Furthermore, in the open field test NA-treated rats displayed increased locomotor activity. These results suggest that prior neuroinflammatory episodes might result in subtle but persistent changes in microglial cells that could determine the response to future challenges such as stressful events.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Microbial neuraminidase induces TLR4-dependent long-term immune priming in the brain

Innate immune memory explains the plasticity of immune responses after repeated immune stimulation, leading to either enhanced or suppressed immune responses. This process has been extensively reported in peripheral immune cells and also, although modestly, in the brain. Here we explored two relevant aspects of brain immune priming: its persistence over time and its dependence on TLR receptors. For this purpose, we used an experimental paradigm consisting in applying two inflammatory stimuli three months apart. Wild type, toll-like receptor (TLR) 4 and TLR2 mutant strains were used. The priming stimulus was the intracerebroventricular injection of neuraminidase (an enzyme that is present in various pathogens able to provoke brain infections), which triggers an acute inflammatory process in the brain. The second stimulus was the intraperitoneal injection of lipopolysaccharide (a TLR4 ligand) or Pam3CSK4 (a TLR2 ligand). One day after the second inflammatory challenge the immune response in the brain was examined. In wild type mice, microglial and astroglial density, as well as the expression of 4 out of 5 pro-inflammatory genes studied (TNFα, IL1β, Gal-3, and NLRP3), were increased in mice that received the double stimulus compared to those exposed only to the second one, which were initially injected with saline instead of neuraminidase. Such enhanced response suggests immune training in the brain, which lasts at least 3 months. On the other hand, TLR2 mutants under the same experimental design displayed an enhanced immune response quite similar to that of wild type mice. However, in TLR4 mutant mice the response after the second immune challenge was largely dampened, indicating the pivotal role of this receptor in the establishment of immune priming. Our results demonstrate that neuraminidase-induced inflammation primes an enhanced immune response in the brain to a subsequent immune challenge, immune training that endures and that is largely dependent on TLR4 receptor

Training in general skill to work in inclusive educational environments

En este trabajo mostramos cómo a partir de una propuesta holística de integración de los créditos prácticos de dos de las asignaturas de la titulación de Psicopedagogía, se contribuye al desarrollo de competencias transversales tales como: trabajo en equipo, participación activa y autonomía personal y emprendimiento. Competencias que tienen puntos de encuentro con los principios fundamentales del modelo de educación inclusiva. Para ello, se ha tenido en cuenta la valoración aportada por el alumnado a las diferentes competencias transversales tras la realización de un proyecto de investigación e intervención en escenarios reales de atención a la diversidadIn this work we show how from a holistic approach to integration of the practical credits of two of the subjects of the degree in educational psychology, it is contributed to the development of general skills such as: team work, active participation and personal autonomy and entrepreneurship. These competencies have linkages between the fundamental principles of the model of inclusive education. In order to do this, we have taken into account the valuation provided by the students to the different generic skills after carrying out a research project and intervention in real-life environment of attention to diversit

Tutoring as a shared work strategy

Se entiende la labor tutorial como una parte esencial de la responsabilidad de la docencia universitaria en la que se busca establecer una interacción más personalizada entre el equipo docente, los y las agentes sociales y el alumnado mentor con los y las estudiantes, lo que supone adaptar el aprendizaje a sus condiciones y necesidades, tanto individuales como grupales, de tal manera que cada alumno y alumna logre alcanzar las competencias requeridas para asumir un proyecto de trabajo a realizar en la titulación de Grado de Educación Social. El objetivo general que centra el desarrollo de esta acción innovadora se concreta en detectar las necesidades de acción tutorial del alumnado de Educación Social en el abordaje de un proyecto de trabajo coordinado en el marco de las materias “Animación Sociocultural: proyectos e intervención”, “Métodos de Investigación en Educación Social”, de la titulación de Grado Educación Social. Nuestro propósito es sentar las bases para la elaboración de un plan de acción tutorial universitaria que agrupe las acciones de acompañamiento y seguimiento del profesorado universitario responsable de las materias implicadas, del alumnado mentor y de los y las agentes externas adheridos al proyecto.The tutorial work is an essential part of the responsibility of university teaching in which it seeks to establish a more personalized interaction between the teaching team, social agents and mentors with students, which means adapting the learning to their conditions and needs, both individual and group, so that each student manages to achieve the skills required to take on a project of work to be carried out in the Degree of Social Education. The general objective that focuses the development of this innovative action is concrete in detecting the needs of tutorial action of the students of Social Education in the approach of a project of work coordinated in the framework of the subjects “Sociocultural Animation: projects and intervention”, “Methods of Research in Social Education” of the Degree in Social Education. Our purpose is to lay the foundations for the elaboration of a university tutorial action plan that groups together the actions of accompaniment and follow-up of university professors responsible for the matters involved, of the mentor student and of the external agents attached to the Project

La voz de los profesionales de la educación social en España y Francia: la identidad autopercibida

Even though the specialized education model in France is a reference in the definition of the training model of the first social educators in Spain, both training processes are developed in differentiated ways. Social education in Spain develops and acquires recognition in the university academic environment, when it is legally recognized in 1991 after the establishment of the official university degree of Diploma in Social Education. However, the training of the specialized educator in France does not take place in the university sphere but in Schools and Institutes of Social Work and concludes with the Diploma of State of Specialized Educator. Both studies were adapted to the European Higher Education Area, allocating a credit load of 180 ECTS, however, the Specialized Educator does not hold the same professional category as the social educator in Spain. Thus, the objective of this work is to know social education as a profession from the perception of its professionals through a comparative study between France and Spain, focusing attention on the training process. For this purpose, a qualitative study was carried out using the structured interview as an information collection instrument. The results show that the social educator in Spain recognizes himself more empowered by defining himself as a professional; both groups identify with the functions and competencies in which they have been trained; they emphasize formative deficiencies and show similar difficulties in the exercise of the profession. The conclusions show that professional recognition goes beyond professional identity, implying recognition or social prestige, as well as the need to design a permanent training plan that channels the training deficiencies of both professionals.A pesar de que el modelo de educación especializada en Francia supone un referente en la definición del modelo formativo de los primeros educadores sociales en España, ambos procesos formativos se desarrollan por vías diferenciadas. La educación social en España se desarrolla y adquiere reconocimiento en al ámbito académico universitario, cuando se reconoce legalmente en 1991 tras el establecimiento del título universitario oficial de Diplomado en Educación Social. Sin embargo, la formación del educador especializado en Francia no se desarrolla en el ámbito universitario sino en Escuelas e Institutos de Trabajo Social y concluye con el título de Diploma de Estado de Educador Especializado. Ambos estudios fueron adaptados al Espacio Europeo de Educación Superior destinando una carga crediticia de 180 ECTS, no obstante, el educador especializado no ostenta la misma categoría profesional que el educador social en España. Así pues, el objetivo de este trabajo es conocer la educación social como profesión desde la percepción de sus profesionales a través de un estudio comparado entre Francia y España, centrando la atención en el proceso formativo. Para ello se llevó a cabo un estudio cualitativo empleando la entrevista estructurada como instrumento de recogida de información. Los resultados muestran que el educador social en España se reconoce más empoderado al definirse a sí mismo como profesional; ambos colectivos se identifican con las funciones y competencias en las que han sido formados; destacan carencias formativas y manifiestan similares dificultades en el ejercicio de la profesión. Las conclusiones indican que el reconocimiento profesional va más allá de la identidad profesional, implicando el reconocimiento o prestigio social, así como la necesidad de diseñar un plan de formación permanente que canalice las carencias formativas de ambos profesionales