Three Pillars of Modern Western Culture

An announcement of Three Pillars of Modern Western Culture by William H. Pastor

Gain-of-Function Effects of Mutant p53 Explored Using a Three-Dimensional Culture Model of Breast Cancer

p53 is the most frequent target for mutation in human tumors and mutation at this locus is a common and early event in breast carcinogenesis. Breast tumors with mutated p53 often contain abundant levels of this mutant protein, which has been postulated to actively contribute to tumorigenesis by acquiring pro-oncogenic ("gain-of-function") properties. To elucidate how mutant p53 might contribute to mammary carcinogenesis, we employed a three-dimensional (3D) culture model of breast cancer. When placed in a laminin-rich extracellular matrix, non-malignant mammary epithelial cells form structures highly reminiscent for many aspects of acinar structures found in vivo. On the other hand, breast cancer cells, when placed in the same environment, form highly disorganized and sometimes invasive structures. Modulation of critical oncogenic signaling pathways has been shown to phenotypically revert breast cancer cells to a more acinar-like morphology. We examined the role of mutant p53 in this context by generating stable, regulatable p53 shRNA derivatives of mammary carcinoma cell lines to deplete endogenous mutant p53. We demonstrated that, depending on the cellular context, mutant p53 depletion is sufficient to significantly reduce invasion or in some cases actually induce a phenotypic reversion to more acinar-like structures in breast cancer cells grown in 3D culture. Additionally, using stable overexpression of a panel of tumor-derived p53 mutants in non-malignant mammary epithelial cells, we found that mutant p53 is sufficient to disrupt normal acinar morphogenesis. Genome-wide expression analysis identified the mevalonate pathway as significantly upregulated by mutant p53. Statins and sterol biosynthesis intermediates revealed that this pathway is both necessary and sufficient for the phenotypic effects of mutant p53 on mammary tissue architecture. We then showed that mutant p53 associates with sterol gene promoters at least partly via SREBP transcription factors. Finally, p53 mutation correlates with highly expressed mevalonate pathway genes in human breast tumors and elevated expression of the mevalonate pathway correlates with a poor prognosis in breast cancer. We also queried a number of pathways/proteins that had previously been implicated in breast cancer and shown to be sufficient to bring about a phenotypic reversion in 3D culture to search for additional mechanisms by which mutant p53 might contribute to mammary carcinogenesis. Using this approach, we identified integrin β4 as a novel target of mutant p53 in breast cancer cells and demonstrated that stable knockdown of integrin β4 is sufficient to dramatically reduce invasive processes in breast cancer cells grown in 3D culture. We also show that mutant p53 associates with the promoter of ITGB4, the gene encoding integrin β4. Finally, we demonstrated that inhibition of NF-κB, a downstream mediator of integrin β 4 signaling, can mimic the phenotypic effects of mutant p53 depletion. These findings contribute to our understanding of breast carcinogenesis and may offer novel prognostic indicators and therapeutic targets for tumors bearing mutations in p53

Modelling languages quality evaluation by taxonomic analysis: a preliminary proposal

El paradigma de la ingeniería dirigida por modelos (MDE por sus siglas en inglés) promueve el uso de modelos conceptuales en procesos de ingeniería e investigación sobre sistemas de información. Como productos de ingeniería los modelos conceptuales deben tener calidad, la cual aplica tanto a los modelos conceptuales como los lenguajes de modelado empleados para construir dichos modelos. Debido a los múltiples retos, divergencias y tendencias para evaluación y aseguramiento de la calidad en contextos MDE, una forma para ejecutar un proceso de evaluación de la calidad es usar una técnica donde la aplicabilidad y metas de los artefactos de modelado puedan ser contrastadas con los principios esenciales del desarrollo de sistemas de información. Este trabajo formula un conjunto de requisitos conceptuales y metodológicos para un marco de evaluación de la calidad de lenguajes de modelado con el potencial de abordar algunos de los retos abiertos de calidad en MDE. Para este propósito, se propone usar principios del popular marco de trabajo Zachman para sistemas de información, como una herramienta taxonómica aplicada sobre artefactos de modelado usados en un desarrollo de un sistema de información, en aras de ejecutar procedimientos analíticos sobre modelos alineados con una arquitectura de referencia para sistemas de información, y con razonamientos ontológicos. En este trabajo se expone cómo el marco Zachman soporta análisis sobre modelos para propósitos de calidad por su administración nativa de la semántica.The Model-Driven Engineering (mde) paradigm promotes the usage of conceptual models in information systems (is) engineering and research. As engineering products, conceptual models must have quality, which applies on both conceptual models and modeling language employed to build them. This paper presents a modeling language quality evaluation framework. This framework uses the principles from the popular Zachman framework for information systems as a taxonomic tool applied over modeling rtifacts used in an information system development. The purpose of this taxonomic tool is to perform analytic procedures that are aligned with an is reference architecture and ontological reasoning. Throughout this work, we describe how the Zachman framework supports analytics over modeling languages for quality purposes by its native management of semantics

Cultura ambiental y su relación con la contaminación del medio ambiente, en una municipalidad del Perú - 2021

La investigación realizada permitió determinar la relación que existe entre la Cultura Ambiental y la Contaminación del Medio Ambiente, en una Institución Municipal2021, la investigación fue desarrollada en el ámbito del casco urbano, basada en una investigación de tipo descriptiva comparativa y correlacional; se consideró una población de 5128 habitantes y una muestra de 160 participantes de la misma población, teniendo en cuenta a un representante por cada vivienda, considerando algunos criterios de inclusión y exclusión, como edad, grado de instrucción y estado de salud mental, para una mejor comprensión del instrumento aplicado. Los datos recogidos, mediante instrumento estadísticamente validado, con prueba estadística de Alfa de Cronbach, fueron sometido a un posterior análisis descriptivo y estadístico, mediante el programa SPSS versión 25. Se concluye que, en una Municipalidad del Perú 2021, existe relación significativa, entre la Cultura Ambiental y Contaminación del Medio Ambiente, verificado estadísticamente, Rho de Spearman de 0,938, usando un nivel de significancia < 5%. Con un p= 0.000

TFAP2C regulates transcription in human naive pluripotency by opening enhancers.

Naive and primed pluripotent human embryonic stem cells bear transcriptional similarity to pre- and post-implantation epiblast and thus constitute a developmental model for understanding the pluripotent stages in human embryo development. To identify new transcription factors that differentially regulate the unique pluripotent stages, we mapped open chromatin using ATAC-seq and found enrichment of the activator protein-2 (AP2) transcription factor binding motif at naive-specific open chromatin. We determined that the AP2 family member TFAP2C is upregulated during primed to naive reversion and becomes widespread at naive-specific enhancers. TFAP2C functions to maintain pluripotency and repress neuroectodermal differentiation during the transition from primed to naive by facilitating the opening of enhancers proximal to pluripotency factors. Additionally, we identify a previously undiscovered naive-specific POU5F1 (OCT4) enhancer enriched for TFAP2C binding. Taken together, TFAP2C establishes and maintains naive human pluripotency and regulates OCT4 expression by mechanisms that are distinct from mouse

Evaluating the quality of a set of modelling languages used in combination: A method and a tool

[EN] Modelling languages have proved to be an effective tool to specify and analyse various perspectives of enterprises and information systems. In addition to modelling language designs, works on model quality and modelling language quality evaluation have contributed to the maturity of the model-driven engineering (MDE) field. Although consolidated knowledge on quality evaluation is still relevant to this scenario, in previous works, we have identified misalignments between the topics that academia is addressing and the needs of industry in applying MDE, thus identifying some remaining challenges. In this paper, we focus on the need for a method to evaluate the quality of a set of modelling languages used in combination within a MDE environment. This paper presents MMQEF (Multiple Modelling language Quality Evaluation Framework), describing its foundations, presenting its method components and discussing its trade-offs. (C) 2018 Elsevier Ltd. All rights reserved.This work was supported by COLCIENCIAS (Colombia) (grant 512, 2010); the European Commision FP7 Project CaaS (611351).Giraldo-Velásquez, FD.; España Cubillo, S.; Giraldo, WJ.; Pastor López, O. (2018). Evaluating the quality of a set of modelling languages used in combination: A method and a tool. Information Systems. 77:48-70. https://doi.org/10.1016/j.is.2018.06.002S48707

The Behaviour of 5-Hydroxymethylcytosine in Bisulfite Sequencing

Background: We recently showed that enzymes of the TET family convert 5-mC to 5-hydroxymethylcytosine (5-hmC) in DNA. 5-hmC is present at high levels in embryonic stem cells and Purkinje neurons. The methylation status of cytosines is typically assessed by reaction with sodium bisulfite followed by PCR amplification. Reaction with sodium bisulfite promotes cytosine deamination, whereas 5-methylcytosine (5-mC) reacts poorly with bisulfite and is resistant to deamination. Since 5-hmC reacts with bisulfite to yield cytosine 5-methylenesulfonate (CMS), we asked how DNA containing 5-hmC behaves in bisulfite sequencing. Methodology/Principal Findings: We used synthetic oligonucleotides with different distributions of cytosine as templates for generation of DNAs containing C, 5-mC and 5-hmC. The resulting DNAs were subjected in parallel to bisulfite treatment, followed by exposure to conditions promoting cytosine deamination. The extent of conversion of 5-hmC to CMS was estimated to be 99.7%. Sequencing of PCR products showed that neither 5-mC nor 5-hmC undergo C-to-T transitions after bisulfite treatment, confirming that these two modified cytosine species are indistinguishable by the bisulfite technique. DNA in which CMS constituted a large fraction of all bases (28/201) was much less efficiently amplified than DNA in which those bases were 5-mC or uracil (the latter produced by cytosine deamination). Using a series of primer extension experiments, we traced the inefficient amplification of CMS-containing DNA to stalling of Taq polymerase at sites of CM

Uso del software Villaplanet y su relación con el nivel de comprensión lectora de los estudiantes del IV y V ciclos de la Institución Educativa N° 43070 de Omate, Región Moquegua en el año 2019

El presente estudio de investigación tiene como propósito determinar la relación que existe entre el uso del software Villaplanet y la comprensión lectora de los estudiantes del IV y V ciclos de la Institución Educativa N° 43070 de la localidad de Omate en la Provincia General Sánchez Cerro en la región Moquegua en el año 2019. Por tanto, la presente investigación es de nivel correlacional, la misma que tiene por objetivo medir el grado de relación significativa que existe entre dos variables; asimismo la investigación es de tipo básica, ya que está orientado a la búsqueda de nuevos conocimientos y campos de la investigación. La población de estudio de la investigación está conformada por estudiantes del nivel primaria, correspondientes al IV y V ciclos (3ro, 4to, 5to y 6to grados) de la Institución Educativa N° 43070 de Omate, que hacen un total de 48 estudiantes, los cuales han sido seleccionados de forma no probabilística y a criterio de los investigadores. Luego del análisis estadístico correspondiente se encuentra que existe relación directamente significativa entre los resultados, encontramos relación significativa entre el uso del software Villaplanet y la comprensión lectora de los estudiantes del IV y V ciclos de la Institución Educativa N° 43070 de la localidad de Omate en la Provincia General Sánchez Cerro en la región Moquegua en el año 2019. Con un valor de 0.928, siendo esta una correlación alta de acuerdo al coeficiente de correlación de Spearman. Lo cual significa que, el uso del software Villaplanet, influye de forma significativa y se relaciona con los niveles de comprensión lectora de los estudiantes. Es decir, los estudiantes que usan y manejan este software, presentan mejores niveles de comprensión lectora