Cédula, 1778-07-09

Copia digital. Valladolid : Junta de Castilla y León. Consejería de Cultura y Turismo, 2012-2013Certifica la copia, Antonio Martinez SalazarTexto fechado en Aranjuez, 9 de Julio de 1778Sign.: [ ]6Port. con esc. real xil

Afectos y consideraciones devotas, y eficacissimas, añadidas a los Exercicios de N.P. S. Ignacio de Loyola, fundador de la Compañía de Jesus

Sign.: A-P12, Q11.Contiene: Va al principio una breve noticia del Libro de los Exercicios, y al último una Instrucción para la confession general, ò particular ; y algunas Consideraciones para antes, y despés de la Comunio

Escudo de la más constante fee, y lealtad

Sign.: A-Z6, 2A-2E6, 2F3Ejemplar con portada, grabada por Braulio González, perteneciente a la impresión de 1762 de El Fuero, privilegios, franquezas, y libertades de los cavalleros hijos dalgo de el muy noble, y muy leal Señorío de Vizcaya... Ver ATV 2656Digitalización. Vitoria-Gasteiz : Fundación Sancho el Sabio, 2008Digitalización. Vitoria-Gasteiz : Archivos y Bibliotecas, Febrero 199

Arbol de la nobilísima y antigua Casa de Abellaneda y de los que del descienden [Manuscrito]

Manuscrito fechado en 1625Incluye varios árboles genealógicos con escudos de armasPapeles de la nobleza de D. Jesús de Abellaneda Manrrique nattural de la Villa de ConsttanttinaDigitalización. Vitoria-Gasteiz : Fundación Sancho el Sabio, 2008Digitalización. Vitoria-Gasteiz : Archivos y Bibliotecas, Febrero 1996Pie

Predicting Phenotypic Diversity and the Underlying Quantitative Molecular Transitions

During development, signaling networks control the formation of multicellular patterns. To what extent quantitative fluctuations in these complex networks may affect multicellular phenotype remains unclear. Here, we describe a computational approach to predict and analyze the phenotypic diversity that is accessible to a developmental signaling network. Applying this framework to vulval development in C. elegans, we demonstrate that quantitative changes in the regulatory network can render ~500 multicellular phenotypes. This phenotypic capacity is an order-of-magnitude below the theoretical upper limit for this system but yet is large enough to demonstrate that the system is not restricted to a select few outcomes. Using metrics to gauge the robustness of these phenotypes to parameter perturbations, we identify a select subset of novel phenotypes that are the most promising for experimental validation. In addition, our model calculations provide a layout of these phenotypes in network parameter space. Analyzing this landscape of multicellular phenotypes yielded two significant insights. First, we show that experimentally well-established mutant phenotypes may be rendered using non-canonical network perturbations. Second, we show that the predicted multicellular patterns include not only those observed in C. elegans, but also those occurring exclusively in other species of the Caenorhabditis genus. This result demonstrates that quantitative diversification of a common regulatory network is indeed demonstrably sufficient to generate the phenotypic differences observed across three major species within the Caenorhabditis genus. Using our computational framework, we systematically identify the quantitative changes that may have occurred in the regulatory network during the evolution of these species. Our model predictions show that significant phenotypic diversity may be sampled through quantitative variations in the regulatory network without overhauling the core network architecture. Furthermore, by comparing the predicted landscape of phenotypes to multicellular patterns that have been experimentally observed across multiple species, we systematically trace the quantitative regulatory changes that may have occurred during the evolution of the Caenorhabditis genus

Intermittent exposure to traces of green leaf volatiles triggers a plant response

Plants are known to mount a defensive response when exposed to volatile chemicals from other plants, but the critical concentration required for this response is not known. We showed that intermittent exposure over a period of 3 weeks to trace amounts (less than 140 pptV) of green leaf volatiles emitted by a freshly damaged Arabidopsis plant induced physiological (defensive) responses in undamaged neighbouring plants. These results demonstrated that plants can respond to long-term repeated exposures to subcritical amounts of chemical signals

A putative biomarker signature for clinically effective AKT inhibition: correlation of in vitro, in vivo and clinical data identifies the importance of modulation of the mTORC1 pathway

Our identification of dysregulation of the AKT pathway in ovarian cancer as a platinum resistance specific event led to a comprehensive analysis of in vitro, in vivo and clinical behaviour of the AKT inhibitor GSK2141795. Proteomic biomarker signatures correlating with effects of GSK2141795 were developed using in vitro and in vivo models, well characterised for related molecular, phenotypic and imaging endpoints. Signatures were validated in temporally paired biopsies from patients treated with GSK2141795 in a clinical study. GSK2141795 caused growth-arrest as single agent in vitro, enhanced cisplatin-induced apoptosis in vitro and reduced tumour volume in combination with platinum in vivo. GSK2141795 treatment in vitro and in vivo resulted in ~50-90% decrease in phospho-PRAS40 and 20-80% decrease in fluoro-deoxyglucose (FDG) uptake. Proteomic analysis of GSK2141795 in vitro and in vivo identified a signature of pathway inhibition including changes in AKT and p38 phosphorylation and total Bim, IGF1R, AR and YB1 levels. In patient biopsies, prior to treatment with GSK2141795 in a phase 1 clinical trial, this signature was predictive of post-treatment changes in the response marker CA125. Development of this signature represents an opportunity to demonstrate the clinical importance of AKT inhibition for re-sensitisation of platinum resistant ovarian cancer to platinum

Quercetin elevates p27Kip1 and arrests both primary and HPV16 E6/E7 transformed human keratinocytes in G1

Our previous work with primary bovine fibroblasts demonstrated that quercetin, a potent mutagen found in high levels in bracken fern (Pteridium aquilinum), arrested cells in G1 and G2/M, in correlation with p53 activation. The expression of bovine papillomavirus type 4 (BPV-4) E7 overcame this arrest and lead to the development of tumorigenic cells lines (Beniston et al., 2001). Given the possible link between papillomavirus infection, bracken fern in the diet and cancer of the upper gastrointestinal (GI) tract in humans, we investigated whether a similar situation would occur in human cells transformed by human papillomavirus type 16 (HPV-16) oncoproteins. Quercetin arrested primary human foreskin keratinocytes in G1. Arrest was linked to an elevation of the cyclin-dependent kinase inhibitor (cdki) p27Kip1. Expression of the HPV16 E6 and E7 oncoproteins in transformed cells failed to abrogate cell cycle arrest. G1 arrest in the transformed cells was also linked to an increase of p27Kip1 with a concomitant reduction of cyclin E-associated kinase activity. This elevation of p27Kip1 was due not only to increased protein half-life, but also to increased mRNA transcription

Real Cédula, 1782-06-02

Copia firmada por Antonio Martínez SalazarSign.: [ ]1, A17Port. con esc. real xil