Chutzpah

A Review of Chutzpah by Alan M. Dershowit

Remodelatge de la cromatina durant la inducció per progesterona del promotor de l'MMTV

Per a comprendre els mecanismes que governen l'expressió dels gens inclosos en els genomes eucariòtics és necessari prendre en consideració la manera en què les regions reguladores d'aquests gens estan organitzades en la cromatina. Les diferències en l'organització de la cromatina i en les modificacions químiques dels components de la cromatina expliquen els diferents patrons de l'expressió gènica en diversos tipus de cèll. ules i la seva resposta específica a senyals externs. Basant-nos en els nostres estudis sobre la inducció hormonal del promotor del mouse mammary tumour virus (MMTV), podem concloure que la seqüència nucleotídica primària determina no solament la manera en què la doble hèlix de DNA envolta l'octàmer d'histona, i així l'accessibilitat de punts d'unió per als factors de transcripció, sinó també la manera en què aquests factors estableixen sinergismes i la naturalesa del remodelatge de la cromatina dependent d'ATP. A més, la senyalització via crosstalk amb cascades de cinases citoplasmàtiques canvia l'estructura de la cromatina en els gens diana i és fonamental per a la correcta regulació a través de receptors d'hormones esteroidees.Understanding the mechanisms governing the expression of the genes encompassed in the eukaryotic genomes requires a careful consideration of the way regulatory regions of these genes are packaged in chromatin. Differences in the chromatin organization and in the chemical modifications of chromatin components account for the different patterns of gene expression in various cell types and for their specific response to external signals. Based on our studies on the hormonal induction of mouse mammary tumour virus (MMTV) promoter we conclude that the primary nucleotide sequence determines not only the way theDNAdouble helix wraps around the histone octamer, and so the accessibility of binding sites for transcription factors, but also the way these factors synergize and the nature of the ATP-dependent chromatin remodelling. Moreover, signalling via crosstalk with cytoplasmic kinase cascades changes the chromatin structure of target genes and is essential for proper regulation by steroid hormone receptors

El “Castillo de Senta” y la frontera. Continuidades y discontinuidades en el espacio, en el tiempo y entre disciplinas

In this paper we present and analyze unpublished sources from Archivo General de Indias related to the construction of a “castillo fortaleza” in the “Valle de Senta” by mid-17th century. Its location, about ten “leguas” from the town of Humahuaca, coincides with the archaeological site academically recognized as an Inka fortress. Based on this case study we examine the continuities and discontinuities in the eastern regionof Quebrada de Humahuaca, through time and territory. The concept of frontier enables us to rethink the relationship between History and Archaeology, regarding the study of the early centuries of the Spanish conquest in the region under study.En este trabajo presentamos y analizamos documentación inédita procedente del Archivo General de Indias que fecha la construcción de un “castillo fortaleza” en el “Valle del Senta”, a mediados del siglo XVII. Su localización, aproximadamente “a diez leguas” del pueblo de Humahuaca, es coincidente con el emplazamiento de un yacimiento arqueológico reconocido académicamente como una fortaleza incaica.A partir de este caso de estudio, examinamos las continuidades y discontinuidades en la región oriental de la Quebrada de Humahuaca a través del tiempo y del territorio. Tomamos como eje de análisis el concepto de frontera pues nos permite pensar en la relación entre Historia y Arqueología en lo que concierne al estudio de los primeros siglos de la conquista española en nuestra región de estudio

Building pathway clusters from Random Forests classification using class votes

<p>Abstract</p> <p>Background</p> <p>Recent years have seen the development of various pathway-based methods for the analysis of microarray gene expression data. These approaches have the potential to bring biological insights into microarray studies. A variety of methods have been proposed to construct networks using gene expression data. Because individual pathways do not act in isolation, it is important to understand how different pathways coordinate to perform cellular functions. However, there are no published methods describing how to build pathway clusters that are closely related to traits of interest.</p> <p>Results</p> <p>We propose to build pathway clusters from pathway-based classification methods. The proposed methods allow researchers to identify clusters of pathways sharing similar functions. These pathways may or may not share genes. As an illustration, our approach is applied to three human breast cancer microarray data sets. We found that our methods yielded consistent and interpretable results for these three data sets. We further investigated one of the pathway clusters found using PubMatrix. We found that informative genes in the pathway clusters do have more publications with keywords, like estrogen receptor, compared with informative genes in other top pathways. In addition, using the shortest path analysis in GeneGo's MetaCore and Human Protein Reference Database, we were able to identify the links which connect the pathways without shared genes within the pathway cluster.</p> <p>Conclusion</p> <p>Our proposed pathway clustering methods allow bioinformaticians and biologists to investigate how informative genes within pathways are related to each other and understand possible crosstalk between pathways in a cluster. Therefore, building pathway clusters may lead to a better understanding of molecular mechanisms affecting a trait of interest, and help generate further biological hypotheses from gene expression data.</p

The Gtpase Rho Controls a P53-Dependent Survival Checkpoint during Thymopoiesis

During the early stages of thymopoiesis, cell survival is controlled by cytokines that regulate the expression of antiapoptotic proteins such as Bcl-2. At the pre-T cell stage, a critical checkpoint for β chain selection is monitored by the tumor suppressor p53: pre-T cells can survive and differentiate when p53 is removed genetically or when its proapoptotic function is inactivated physiologically as a consequence of signaling through the pre-T cell receptor complex. Previous work has shown that the guanine nucleotide binding protein Rho controls cell survival in T cell progenitors. Here we define the survival pathways controlled by Rho in pre-T cells and show that this GTPase is a pivotal regulator of the p53-mediated checkpoint operating at the time of β selection: loss of Rho function results in apoptosis in pre-T cells, but this cell death is prevented by loss of p53. The prevention of cell death by loss of p53 restored numbers of early T cell progenitors but did not fully restore thymic cellularity. Further analysis revealed that loss of Rho function caused survival defects in CD4/8 double-positive thymocytes that is independent of p53 but can be prevented by ectopic expression of Bcl-2. These studies highlight that the GTPase Rho is a crucial component of survival signaling pathways in at least two different thymocyte subpopulations: Rho controls the p53 survival checkpoint in pre-T cells and is also crucial for a p53 independent survival signaling pathway in CD4/8 double positives

Skin friction blistering: computer model

BACKGROUND/PURPOSE: Friction blisters, a common injury in sports and military operations, can adversely effect or even halt performance. Given its frequency and hazardous nature, recent research efforts appear limited. Blistering can be treated as a delamination phenomenon; similar issues in materials science have been extensively investigated in theory and experiment. An obstacle in studying blistering is the difficulty of conducting experiment on humans and animals. Computer modeling thus becomes a preferred tool. METHOD: This paper used a dynamic non-linear finite-element model with a blister-characterized structure and contact algorithm for outer materials and blister roof to investigate the effects on deformation and stress of an existing blister by changing the friction coefficient and elastic modulus of the material in contact with the blister. RESULTS: Through the dynamics mode and harmonic frequency approach, we demonstrated that the loading frequency leads to dramatic changes of displacement and stress in spite of otherwise similar loading. Our simulations show that an increased friction coefficient does not necessarily result in an increase in either the stress on the hot spot or blister deformation; local maximum friction stress and Von Mises stress exist for some friction coefficients over the wide range examined here. In addition, the stiffness of contact material on blistering is also investigated, and no significant effects on deformation and Von Mises stress are found, again at the range used. The model and method provided here may be useful for evaluating loading environments and contact materials in reducing blistering incidents. CONCLUSION: The coupling finite-element model can predict the effects of friction coefficient and contacting materials' stiffness on blister deformation and hot spot stress

Nuclear role for human Argonaute-1 as an estrogen-dependent transcription coactivator

In mammals, argonaute (AGO) proteins have been characterized for their roles in small RNA mediated posttranscriptional and also in transcriptional gene silencing. Here, we report a different role for AGO1 in estradiol-triggered transcriptional activation in human cells. We show that in MCF-7 mammary gland cells, AGO1 associates with transcriptional enhancers of estrogen receptor α (ERα) and that this association is up-regulated by treating the cells with estrogen (E2), displaying a positive correlation with the activation of these enhancers.Moreover, we show that AGO1 interacts with ERα and that this interaction is also increased by E2 treatment, but occurs in the absence of RNA. We show that AGO1 acts positively as a coactivator in estradiol-triggered transcription regulation by promoting ERα binding to its enhancers. Consistently, AGO1 depletion decreases long-range contacts between ERα enhancers and their target promoters. Our results point to a role of AGO1 in transcriptional regulation in human cells that is independent from small RNA binding.Fil: Gómez Acuña, Luciana Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Nazer, Ezequiel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Rodríguez Seguí, Santiago Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Pozzi, María Berta. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Buggiano, Valeria Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Marasco, Luciano Edmundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Agirre, Eneritz. Karolinska Huddinge Hospital. Karolinska Institutet; SueciaFil: He, Cody. University of Chicago; Estados UnidosFil: Alló, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Kornblihtt, Alberto Rodolfo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentin

Transcriptomic changes in human breast cancer progression as determined by serial analysis of gene expression

INTRODUCTION: Genomic and transcriptomic alterations affecting key cellular processes such us cell proliferation, differentiation and genomic stability are considered crucial for the development and progression of cancer. Most invasive breast carcinomas are known to derive from precursor in situ lesions. It is proposed that major global expression abnormalities occur in the transition from normal to premalignant stages and further progression to invasive stages. Serial analysis of gene expression (SAGE) was employed to generate a comprehensive global gene expression profile of the major changes occurring during breast cancer malignant evolution. METHODS: In the present study we combined various normal and tumor SAGE libraries available in the public domain with sets of breast cancer SAGE libraries recently generated and sequenced in our laboratory. A recently developed modified t test was used to detect the genes differentially expressed. RESULTS: We accumulated a total of approximately 1.7 million breast tissue-specific SAGE tags and monitored the behavior of more than 25,157 genes during early breast carcinogenesis. We detected 52 transcripts commonly deregulated across the board when comparing normal tissue with ductal carcinoma in situ, and 149 transcripts when comparing ductal carcinoma in situ with invasive ductal carcinoma (P < 0.01). CONCLUSION: A major novelty of our study was the use of a statistical method that correctly accounts for the intra-SAGE and inter-SAGE library sources of variation. The most useful result of applying this modified t statistics beta binomial test is the identification of genes and gene families commonly deregulated across samples within each specific stage in the transition from normal to preinvasive and invasive stages of breast cancer development. Most of the gene expression abnormalities detected at the in situ stage were related to specific genes in charge of regulating the proper homeostasis between cell death and cell proliferation. The comparison of in situ lesions with fully invasive lesions, a much more heterogeneous group, clearly identified as the most importantly deregulated group of transcripts those encoding for various families of proteins in charge of extracellular matrix remodeling, invasion and cell motility functions

Targeted Deletion of p73 in Mice Reveals Its Role in T Cell Development and Lymphomagenesis

Transcriptional silencing of the p73 gene through methylation has been demonstrated in human leukemias and lymphomas. However, the role of p73 in the malignant process remains to be explored. We show here that p73 acts as a T cell-specific tumor suppressor in a genetically defined mouse model, and that concomitant ablation of p53 and p73 predisposes mice to an increased incidence of thymic lymphomas compared to the loss of p53 alone. Our results demonstrate a causal role for loss of p73 in progression of T cell lymphomas to the stage of aggressive, disseminated disease. We provide evidence that tumorigenesis in mice lacking p53 and p73 proceeds through mechanisms involving altered patterns of gene expression, defects in early T cell development, impaired apoptosis, and the ensuing accumulation of chromosomal aberrations. Collectively, our data imply that tumor suppressive properties of p73 are highly dependent on cellular context, wherein p73 plays a major role in T cell development and neoplasia