A DR4:tBID axis drives the p53 apoptotic response by promoting oligomerization of poised BAX

The cellular response to p53 activation varies greatly in a stimulus‐ and cell type‐specific manner. Dissecting the molecular mechanisms defining these cell fate choices will assist the development of effective p53‐based cancer therapies and also illuminate fundamental processes by which gene networks control cellular behaviour. Using an experimental system wherein stimulus‐specific p53 responses are elicited by non‐genotoxic versus genotoxic agents, we discovered a novel mechanism that determines whether cells undergo proliferation arrest or cell death. Strikingly, we observe that key mediators of cell‐cycle arrest (p21, 14‐3‐3σ) and apoptosis (PUMA, BAX) are equally activated regardless of outcome. In fact, arresting cells display strong translocation of PUMA and BAX to the mitochondria, yet fail to release cytochrome C or activate caspases. Surprisingly, the key differential events in apoptotic cells are p53‐dependent activation of the DR4 death receptor pathway, caspase 8‐mediated cleavage of BID, and BID‐dependent activation of poised BAX at the mitochondria. These results reveal a previously unappreciated role for DR4 and the extrinsic apoptotic pathway in cell fate choice following p53 activation.Fil: Henry, Ryan E. State University Of Colorado-boulder; Estados UnidosFil: Andrysik, Zdenek. State University Of Colorado-boulder; Estados UnidosFil: Paris, Ramiro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mar del Plata. Instituto de Investigaciones Biológicas; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Biológicas; Argentina. State University Of Colorado-boulder; Estados UnidosFil: Galbraith, Matthew D.. State University Of Colorado-boulder; Estados UnidosFil: Espinosa, Joaquín M.. State University Of Colorado-boulder; Estados Unido

Simulación prospectiva del crecimiento urbano en la Comunidad Autónoma de Madrid a partir de modelos basados en autómatas celulares y modelos basados en EMC

En el presente trabajo se analizan los resultados de varias simulaciones prospectivas de crecimiento urbano, entre los años 2000 y 2020, realizadas en la Comunidad de Madrid, aplicando dos modelos diferentes: uno basado en Autómatas Celulares (AC) y otro en técnicas de Evaluación MultiCriterio (EMC). El objetivo es comparar los resultados de las simulaciones de ambos modelos para detectar si se aproximan o están fuertemente influidos por la técnica empleada. Esto también permitiría, en cierta forma, evaluar los modelos desarrollados y su utilidad, pudiendo generar una cartografía de los resultados más robustos, es decir, de localizaciones que reiteradamente aparecen en las distintas simulaciones como las más apropiadas para desarrollar una futura ocupación urbana. En este caso concreto, se ha podido comprobar la escasa coincidencia entre resultados, evidenciando la necesidad, por un lado, de utilizar metodologías de comparación de mapas más flexibles, que permitan valorar mejor las semejanzas/diferencias encontradas, y, por otro, de detectar particularidades de los modelos que estén condicionando los resultados e, inclusive, deficiencias en su desarrollo.Proyecto SIMURBAN2: Instrumentos de Geosimulación y planificación ambiental en la ordenación territorial de ámbitos metropolitanos. Aplicación a escalas intermedias (Ref.: CSO2012-38158-C02-01)

Revisión bibliográfica de implantología bucofacial del año 2009. 1ª parte

Debido al amplio número de publicaciones que existen sobre Implantología Bucofacial, resultadifícil para el odontólogo seleccionar y leer de forma crítica una cantidad suficiente de artículos que puedan aportarle una información útil para su praxis diaria. En este artículo se pretende sintetizar la información más relevante que se encuentra en las revistas indexadas de la especialidad publicadas durante el año 2009

Revisión bibliográfica de implantología bucofacial del año 2009. 2ª parte

Debido al amplio número de publicaciones que existen sobre Implantología Bucofacial, resulta difícil para el odontólogo seleccionar y leer de forma crítica una cantidad suficiente de artículos que puedan aportarle una información útil para su praxis diaria. En este artículo pretendemos sintetizar la información más relevante que se encuentra en las revistas indexadas de la especialidad publicadas el año 2009

Revisión bibliográfica de implantología bucofacial del año 2009. 2ª parte

Debido al amplio número de publicaciones que existen sobre Implantología Bucofacial, resulta difícil para el odontólogo seleccionar y leer de forma crítica una cantidad suficiente de artículos que puedan aportarle una información útil para su praxis diaria. En este artículo pretendemos sintetizar la información más relevante que se encuentra en las revistas indexadas de la especialidad publicadas el año 2009

Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity

Trisomy 21 (T21) causes Down syndrome (DS), a condition characterized by high prevalence of autoimmune disorders. However, the molecular and cellular mechanisms driving this phenotype remain unclear. Building upon our previous finding that T cells from people with DS show increased expression of interferon (IFN)stimulated genes, we have completed a comprehensive characterization of the peripheral T cell compartment in adults with DS with and without autoimmune conditions. CD8+ T cells from adults with DS are depleted of naïve subsets and enriched for differentiated subsets, express higher levels of markers of activation and senescence (e.g., IFN-γ, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-α). Conventional CD4+ T cells display increased differentiation, polarization toward the Th1 and Th1/17 states, and overproduction of the autoimmunity-related cytokines IL-17A and IL-22. Plasma cytokine analysis confirms elevation of multiple autoimmunity-related cytokines (e.g., TNF-α, IL17A–D, IL-22) in people with DS, independent of diagnosis of autoimmunity. Although Tregs are more abundant in DS, functional assays show that CD8+ and CD4+ effector T cells with T21 are resistant to Treg-mediated suppression, regardless of Treg karyotype. Transcriptome analysis of white blood cells and T cells reveals strong signatures of T cell differentiation and activation that correlate positively with IFN hyperactivity. Finally, mass cytometry analysis of 8 IFN-inducible phosphoepitopes demonstrates that T cell subsets with T21 show elevated levels of basal IFN signaling and hypersensitivity to IFN-α stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS.Fil: Araya, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Waugh, Katherine A.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Sullivan, Kelly D.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Núñez, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Roselli, Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Smith, Keith P.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Granrath, Ross E.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Rachubinski, Angela L.. University of Colorado; Estados UnidosFil: Enriquez Estrada, Belinda. University Of Colorado. School Of Medicine.; Estados UnidosFil: Butcher, Eric T.. University of Colorado; Estados UnidosFil: Minter, Ross. University of Colorado; Estados UnidosFil: Tuttle, Kathryn D.. University of Colorado; Estados UnidosFil: Bruno, Tullia C.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Maccioni, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Espinosa, Joaquín M.. University Of Colorado. School Of Medicine.; Estados Unido

Homozygous R136S mutation in PRNP gene causes inherited early onset prion disease

Altres ajuts: Fundació la Marató de TV3/201821-31Background: More than 40 pathogenic heterozygous PRNP mutations causing inherited prion diseases have been identified to date. Recessive inherited prion disease has not been described to date. Methods: We describe the clinical and neuropathological data of inherited early-onset prion disease caused by the rare PRNP homozygous mutation R136S. In vitro PrP propagation studies were performed using recombinant-adapted protein misfolding cyclic amplification technique. Brain material from two R136S homozygous patients was intracranially inoculated in TgMet129 and TgVal129 transgenic mice to assess the transmissibility of this rare inherited form of prion disease. Results: The index case presented symptoms of early-onset dementia beginning at the age of 49 and died at the age of 53. Neuropathological evaluation of the proband revealed abundant multicentric PrP plaques and Western blotting revealed a ~ 8 kDa protease-resistant, unglycosylated PrP fragment, consistent with a Gerstmann-Sträussler-Scheinker phenotype. Her youngest sibling suffered from progressive cognitive decline, motor impairment, and myoclonus with onset in her late 30s and died at the age of 48. Genetic analysis revealed the presence of the R136S mutation in homozygosis in the two affected subjects linked to homozygous methionine at codon 129. One sibling carrying the heterozygous R136S mutation, linked to homozygous methionine at codon 129, is still asymptomatic at the age of 74. The inoculation of human brain homogenates from our index case and an independent case from a Portuguese family with the same mutation in transgenic mice expressing human PrP and in vitro propagation of PrP studies failed to show disease transmissibility. Conclusion: In conclusion, biallelic R136S substitution is a rare variant that produces inherited early-onset human prion disease with a Gerstmann-Sträussler-Scheinker neuropathological and molecular signature. Even if the R136S variant is predicted to be "probably damaging", heterozygous carriers are protected, at least from an early onset providing evidence for a potentially recessive pattern of inheritance in human prion diseases

Trisomy 21 induces pericentrosomal crowding delaying primary ciliogenesis and mouse cerebellar development.

Trisomy 21, the genetic cause of Down syndrome, disrupts primary cilia formation and function, in part through elevated Pericentrin, a centrosome protein encoded on chromosome 21. Yet how trisomy 21 and elevated Pericentrin disrupt cilia-related molecules and pathways, and the in vivo phenotypic relevance remain unclear. Utilizing ciliogenesis time course experiments combined with light microscopy and electron tomography, we reveal that chromosome 21 polyploidy elevates Pericentrin and microtubules away from the centrosome that corral MyosinVA and EHD1, delaying ciliary membrane delivery and mother centriole uncapping essential for ciliogenesis. If given enough time, trisomy 21 cells eventually ciliate, but these ciliated cells demonstrate persistent trafficking defects that reduce transition zone protein localization and decrease sonic hedgehog signaling in direct anticorrelation with Pericentrin levels. Consistent with cultured trisomy 21 cells, a mouse model of Down syndrome with elevated Pericentrin has fewer primary cilia in cerebellar granule neuron progenitors and thinner external granular layers at P4. Our work reveals that elevated Pericentrin from trisomy 21 disrupts multiple early steps of ciliogenesis and creates persistent trafficking defects in ciliated cells. This pericentrosomal crowding mechanism results in signaling deficiencies consistent with the neurological phenotypes found in individuals with Down syndrome

USP19 modulates cancer cell migration and invasion and acts as a novel prognostic marker in patients with early breast cancer

Tumor cell dissemination in cancer patients is associated with a significant reduction in their survival and quality of life. The ubiquitination pathway plays a fundamental role in the maintenance of protein homeostasis both in normal and stressed conditions and its dysregulation has been associated with malignant transformation and invasive potential of tumor cells, thus highlighting its value as a potential therapeutic target. In order to identify novel molecular targets of tumor cell migration and invasion we performed a genetic screen with an shRNA library against ubiquitination pathway-related genes. To this end, we set up a protocol to specifically enrich positive migration regulator candidates. We identified the deubiquitinase USP19 and demonstrated that its silencing reduces the migratory and invasive potential of highly invasive breast cancer cell lines. We extended our investigation in vivo and confirmed that mice injected with USP19 depleted cells display increased tumor-free survival, as well as a delay in the onset of the tumor formation and a significant reduction in the appearance of metastatic foci, indicating that tumor cell invasion and dissemination is impaired. In contrast, overexpression of USP19 increased cell invasiveness both in vitro and in vivo, further validating our findings. More importantly, we demonstrated that USP19 catalytic activity is important for the control of tumor cell migration and invasion, and that its molecular mechanism of action involves LRP6, a Wnt co-receptor. Finally, we showed that USP19 overexpression is a surrogate prognostic marker of distant relapse in patients with early breast cancer. Altogether, these findings demonstrate that USP19 might represent a novel therapeutic target in breast cancer.Facultad de Ciencias MédicasCentro de Investigaciones Inmunológicas Básicas y Aplicada