N-terminally truncated A beta 4-x proteoforms and their relevance for Alzheimer's pathophysiology

BACKGROUND: The molecular heterogeneity of Alzheimer's amyloid-β (Aβ) deposits extends well beyond the classic Aβ1-40/Aβ1-42 dichotomy, substantially expanded by multiple post-translational modifications that increase the proteome diversity. Numerous truncated fragments consistently populate the brain Aβ peptidome, and their homeostatic regulation and potential contribution to disease pathogenesis are largely unknown. Aβ4-x peptides have been reported as major components of plaque cores and the limited studies available indicate their relative abundance in Alzheimer's disease (AD). METHODS: Immunohistochemistry was used to assess the topographic distribution of Aβ4-x species in well-characterized AD cases using custom-generated monoclonal antibody 18H6-specific for Aβ4-x species and blind for full-length Aβ1-40/Aβ1-42-in conjunction with thioflavin-S and antibodies recognizing Aβx-40 and Aβx-42 proteoforms. Circular dichroism, thioflavin-T binding, and electron microscopy evaluated the biophysical and aggregation/oligomerization properties of full-length and truncated synthetic homologues, whereas stereotaxic intracerebral injections of monomeric and oligomeric radiolabeled homologues in wild-type mice were used to evaluate their brain clearance characteristics. RESULTS: All types of amyloid deposits contained the probed Aβ epitopes, albeit expressed in different proportions. Aβ4-x species showed preferential localization within thioflavin-S-positive cerebral amyloid angiopathy and cored plaques, strongly suggesting poor clearance characteristics and consistent with the reduced solubility and enhanced oligomerization of their synthetic homologues. In vivo clearance studies demonstrated a fast brain efflux of N-terminally truncated and full-length monomeric forms whereas their oligomeric counterparts-particularly of Aβ4-40 and Aβ4-42-consistently exhibited enhanced brain retention. CONCLUSIONS: The persistence of aggregation-prone Aβ4-x proteoforms likely contributes to the process of amyloid formation, self-perpetuating the amyloidogenic loop and exacerbating amyloid-mediated pathogenic pathways

Mitochondrial dysfunction induced by a post-translationally modified amyloid linked to a familial mutation in an alternative model of neurodegeneration

AbstractFamilial British dementia (FBD) is an early-onset non-amyloid-β (Aβ) cerebral amyloidosis that presents with severe cognitive decline and strikingly similar neuropathological features to those present in Alzheimer's disease (AD). FBD is associated with a T to A single nucleotide transition in the stop codon of a gene encoding BRI2, leading to the production of an elongated precursor protein. Furin-like proteolytic processing at its C-terminus releases a longer-than-normal 34 amino acid peptide, ABri, exhibiting amyloidogenic properties not seen in its 23 amino acid physiologic counterpart Bri1–23. Deposited ABri exhibits abundant post-translational pyroglutamate (pE) formation at the N-terminus, a feature seen in truncated forms of Aβ found in AD deposits, and co-exists with neurofibrillary tangles almost identical to those found in AD. We tested the impact of the FBD mutation alone and in conjunction with the pE post-translational modification on the structural properties and associated neurotoxicity of the ABri peptide. The presence of pE conferred to the ABri molecule enhanced hydrophobicity and accelerated aggregation/fibrillization properties. ABri pE was capable of triggering oxidative stress, loss of mitochondrial membrane potential and activation of caspase-mediated apoptotic mechanisms in neuronal cells, whereas homologous peptides lacking the elongated C-terminus and/or the N-terminal pE were unable to induce similar detrimental cellular pathways. The data indicate that the presence of N-terminal pE is not in itself sufficient to induce pathogenic changes in the physiologic Bri1–23 peptides but that its combination with the ABri mutation is critical for the molecular pathogenesis of FBD

El encuentro educativo. Una experiencia dialógica-creativa- gnoseológica

El presente texto se inscribe dentro de la discusión acerca de la producción de conocimiento que se efectúa desde la  visión de la propuesta latinoamericana  de educación popular para analizar  esta situación, se concentra en el  “encuentro dialógico” que está en el  centro de las tesis planteadas desde  esta perspectiva, en la interacción  plural de conocimientos. Es decir en la construcción de la experiencia educativa a partir r del compartir saberes, de su reciprocidad y validación desde el  otro, y de los elementos que se ponen  en juego para que esto suceda, como la  experiencia emocional y la experiencia  gnoseológica

TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling

In patients, non-proliferative disseminated tumour cells (DTCs) can persist in the bone marrow (BM) while other organs (such as lung) present growing metastasis. This suggested that the BM might be a metastasis ‘restrictive soil’ by encoding dormancy-inducing cues in DTCs. Here we show in a head and neck squamous cell carcinoma (HNSCC) model that strong and specific transforming growth factor-β2 (TGF-β2) signalling in the BM activates the MAPK p38α/β, inducing an (ERK/p38)low signalling ratio. This results in induction of DEC2/SHARP1 and p27, downregulation of cyclin-dependent kinase 4 (CDK4) and dormancy of malignant DTCs. TGF-β2-induced dormancy required TGF-β receptor-I (TGF-β-RI), TGF-β-RIII and SMAD1/5 activation to induce p27. In lungs, a metastasis ‘permissive soil’ with low TGF-β2 levels, DTC dormancy was short-lived and followed by metastatic growth. Importantly, systemic inhibition of TGF-β-RI or p38α/β activities awakened dormant DTCs, fuelling multi-organ metastasis. Our work reveals a ‘seed and soil’ mechanism where TGF-β2 and TGF-β-RIII signalling through p38α/β regulates DTC dormancy and defines restrictive (BM) and permissive (lung) microenvironments for HNSCC metastasis.Fil: Bragado, Paloma. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados UnidosFil: Estrada, Yeriel. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados UnidosFil: Parikh, Falguni. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados UnidosFil: Krause, Sarah. University Hospital of Schleswig-Holstein; AlemaniaFil: Capobianco, Carla Sabrina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Farina, Hernán Gabriel. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schewe, Denis M.. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados UnidosFil: Aguirre Ghiso, Julio A.. Mount Sinai School of Medicine. Tisch Cancer Institute; Estados Unido

La fugaz verdad de la experiencia

El ensayo encuentra su sentido en la proximidad que tiene con el acontecimiento, la experiencia formativa y “con lo provisorio de la vida misma.” Surge de la reflexión de la práctica como docente universitario, en la vivencia del educador, en su actuar pedagógico reflexivo. Situado en la dinámica generativa: método/camino/ensayo/travesía/búsqueda/estrategia, se aproxima por medio de la observación y conceptualización a lo efímero, lo contingente, la novedad, la multiplicidad; fundamentado en principios métodológicos que dan cuenta de una iniciación en el pensar complejo. Asumiendo los principios del pensamiento complejo a manera de conceptos sensibilizadores, se busca comprender la interacción educativa. Por último, se desarrollan temáticas emergentes, que pueden ser asumidas en próximas reflexiones e investigaciones sobre las múltiples y diferenciadas experiencias y acontecimientos formativos universitarios.The essay finds its meaning in the proximity it has with the event, the training experience and “the provisional quality of life itself.” It arises from the analysis of his university teacher’s practice, this is, the experience of the educator in his teaching considerations. Located in the generative dynamic: method / path / essay / cruise / search / strategy, it approximates by means of observation and conceptualization to the ephemeral, contingent, novelty, variety; based on methodological principles that account for an initiation in complex thinking. Assuming the principles of complex thinking as sensible producing concepts, it seeks to understand educational interaction. Finally, emerging issues which can be taken into account in future studies and research on the many different learning experiences and university events, are developed.Cet essai s’intéresse à l’événement, l’expérience formative et « le provisoire de la vie elle-même ». Il est issu de la pratique de l’enseignant universitaire, de l’expérience de l’éducateur, dans sa manière pédagogique et réflexive d’agir. Se situant dans la dynamique générative : méthode/chemin/ tentative/recherche/stratégie, il s’approche, de par l’observation et la conceptualisation, de l’éphémère, de la contingence, de la nouveauté, de la multiplicité ;il s’inspire pour cela des principes méthodologiques qui rendent compte d’une initiation à la pensée complexe. En assumant les principes de la pensée complexes compris tels des concepts sensibilisateurs, l’objectif vise à comprendre l’interaction éducative. Enfin, des thématiques émergentes sont développées afin de les considérer au cœur de futures réflexions et travaux concernant les expériences multiples et différenciées et les événements formatifs universitaires.O ensaio encontra o seu significado na proximidade que tem com o evento, formação e experiência “com o provisório da própria vida.” Surge a partir da reflexão da prática como professor universitário, na experiência do educador, em seu ato ensino reflexivo. Localizado no método dinâmico: gerador / caminho / testing / cruzeiro / search / estratégia, é uma aproximação por meio da observação e conceituação à novidade, efêmera, contingente, variedade, com base em princípios metodológicos que conta para uma introdução ao pensamento complexo. Compreender os princípios do pensamento complexo, uma forma de sensibilizar os conceitos, busca compreender a interação educacional. Finalmente, as questões emergentes, que podem ser tomadas em futuros estudos e pesquisas sobre as muitas e diferentes experiências de aprendizagem e eventos universitários

Investigación social comunitaria en contextos conflictivos

The author presents a reflection about the social community research. He introduces the particularities of this knowledge experience, showing the importance of contexts analysis, of meanings which remarks the forms how human beings interact and build their environment, also the possibility of a research which focuses authorizes the recognition of such particularities and the generation of a knowledge with alternative accuracy. © Revista Colombiana de Ciencias Sociales.El autor presenta una reflexión en torno a la investigación social comunitaria. Presenta las particularidades de esta experiencia  de conocimiento, presentando la importancia del análisis de los contextos, de las significaciones que dan cuenta de las formas en las que los seres humanos interaccionan y construyen sus entornos, así como la posibilidad de una investigación cuyo enfoque autorice el reconocimiento de tales singularidades y de la generación de un conocimiento con un tipo de rigurosidad alternativo. © Revista Colombiana de Ciencias Sociales

Professionalization of social educators in latin america. Another reading of the transits between popular education and social pedagogy.

This text is the result of a piece of research, which gives an account of how meetings and dialogues between educational traditions, on the one hand, recount, changes, conflicts, and challenges to face in responding to educational demands that populations, organizations, and social movements present; and, on the other hand, they reveal existing tensions in political and institutional settings, the demands of the labor market of social educators against the academic and formative developments related to its professionalization. The dialogues and exchanges, then, have not but are not alien to these contexts, and it is in them, which the theoretical, methodological, and practical references are configured of current proposals for the training of social educators and for projects of critical social pedagogy in Latin America.El presente texto resultado de investigación da cuenta de cómo los encuentros y diálogos entre tradiciones socioeducativas, por un lado dan cuenta de las transiciones, cambios, conflictos y de los desafíos a enfrentar al responder a las demandas educativas que las poblaciones, organizaciones y movimientos sociales presentan; y, por el otro, ponen de manifiesto las tensiones existentes en los escenarios políticos e institucionales, en las exigencias del mercado laboral de los pedagogos sociales frente a los desarrollos académicos y formativos vinculados a su profesionalización. Los diálogos e intercambios, entonces, no han sino, ni son ajenos a estos contextos, y es en ellos que se vienen configurando los referentes teóricos, metodológicos y práxicos de las actuales propuestas de formación de educadores sociales y de proyectos de pedagogía social crítica en América Latina

Reflexividad dialógica, como experiencia de epistemes sentipensantes y solidarias

Desarrollar prácticas de construcción de conocimientos desde una episteme solidaria - emancipadora requiere de opciones éticas, políticas y epistemológicas explícitas; este desafío, en el contexto inhabilitante e inmovilizante en el que vivimos, exige altas dosis de convivencialidad, imaginación, creatividad y coraje porque tenemos que estar preparados para superar muchas frustraciones y curar las tristezas y desesperanzas, que sufrimos a diario y que nos debilitan y enferman.Developing practices of construction of knowledge from a shared and emancipatory episteme requires explicit, ethical, political, and epistemological choices. This challenge within the disqualifying and immobilizing context we live in, demands a high dose of conviviality, imagination, creativity, and courage since we need to be prepared in order to overcome many frustrations and to heal the sadness and hopelessness, that we experience on a daily basis, weaken and sicken us

Reflexiones de un educador freiriano

It exposed a reflection on the role of education with meaning, where for to seek answers, it is good to work methodically with the students, spending more time to the critical analysis of our languages, our practices and especially our daily life. In this activity we would learn together to observe, compare, select and establish relationships between events and discourses; exercising the right to ask, disagree, criticize, be curious, creative open and democratic. It is certainly a challenge worth taking on, but it is impossible if we do not want it, if we do not restore the creative impulse that allows us to dream of a country where life has value and people have and can become subjects capable of exercising democratically their rights as citizens. All this requires educators high doses of creativity, energy, love, respect, dialogue and solidarity.Se expone una reflexión frente al rol de la educación con sentido,donde para buscar respuestas, es bueno trabajar metódicamentecon los educandos, dedicando más tiempo al análisis crítico denuestros lenguajes, de nuestras prácticas y en especial de nuestravida cotidiana. En esa actividad aprenderíamos juntos a observar,comparar, seleccionar y establecer las relaciones entre los hechos ylos discursos; ejerciendo el derecho a preguntar, discrepar, criticar,a ser curiosos, creativos abiertos y democráticos. Sin duda es un retoque vale la pena asumir, pero es imposible si no lo deseamos, si norestablecemos el impulso creativo que nos permite soñar con un paísdonde la vida tiene valor y las personas tienen y pueden llegar a sersujetos capaces de ejercer democráticamente sus derechos comociudadanos. Todo esto requiere de los educadores altas dosis decreatividad, energía, amor, respeto, diálogo y solidaridad