Genome-wide mapping of ORC and Mcm2p binding sites on tiling arrays and identification of essential ARS consensus sequences in S. cerevisiae

BACKGROUND: Eukaryotic replication origins exhibit different initiation efficiencies and activation times within S-phase. Although local chromatin structure and function influences origin activity, the exact mechanisms remain poorly understood. A key to understanding the exact features of chromatin that impinge on replication origin function is to define the precise locations of the DNA sequences that control origin function. In S. cerevisiae, Autonomously Replicating Sequences (ARSs) contain a consensus sequence (ACS) that binds the Origin Recognition Complex (ORC) and is essential for origin function. However, an ACS is not sufficient for origin function and the majority of ACS matches do not function as ORC binding sites, complicating the specific identification of these sites. RESULTS: To identify essential origin sequences genome-wide, we utilized a tiled oligonucleotide array (NimbleGen) to map the ORC and Mcm2p binding sites at high resolution. These binding sites define a set of potential Autonomously Replicating Sequences (ARSs), which we term nimARSs. The nimARS set comprises 529 ORC and/or Mcm2p binding sites, which includes 95% of known ARSs, and experimental verification demonstrates that 94% are functional. The resolution of the analysis facilitated identification of potential ACSs (nimACSs) within 370 nimARSs. Cross-validation shows that the nimACS predictions include 58% of known ACSs, and experimental verification indicates that 82% are essential for ARS activity. CONCLUSION: These findings provide the most comprehensive, accurate, and detailed mapping of ORC binding sites to date, adding to the emerging picture of the chromatin organization of the budding yeast genome

La garantía contra la evicción : Caracterización y requisitos en el Código Civil y Comercial de la Nación

“Evicción” es un término que proviene de los vocablos evictio y evincere, que hacen referencia una derrota que se produce en un juicio, en especial cuando una sentencia acoge la pretensión de reivindicación de una cosa, a la que se asocia la idea de la victoria del reivindicante. Comprende las situaciones en que la existencia o la extensión el derecho transmitido están expuestas a sufrir las consecuencias de la reclamación de un tercero fundada en un derecho. El art. 1044 del C.C. y C. de la Nación prescribe que la responsabilidad por la evicción asegura la existencia y legitimidad del derecho transmitido. La mejor manera de aproximarse a su caracterización es tener en cuenta su contenido, Presupone que la existencia o extensión del derecho transmitido se ve comprometida por reclamos de terceros que se fundan en un derecho. Es lo que se denomina la turbación del derecho. Si tales reclamaciones prosperan, se produce la privación total o parcial del derecho adquirido. Vale decir la garantía de evicción configura una secuencia: comienza a funcionar cuando acaece la turbación. A partir de ese momento se generan obligaciones del transmitente. En este período inicial, en que se pone en movimiento la garantía, que se ha denominado principio de evicción1, nace la obligación del transmitente de asistir y de defender al adquirente. Se trata de una obligación de hacer. Si la reclamación del tercero es exitosa, opera la privación total o parcial del derecho del adquirente. Se produce el desenlace que se considera como la evicción producida, esto es, el de la pérdida o de la derrota que se corresponden con el significado etimológico del vocablo evicción. A la par de lo señalado, el elenco de obligaciones que se derivan de la garantía se completa con la obligación que tiene el garante de abstenerse de perturbar el derecho transmitido. Es una obligación de no hacer.Facultad de Ciencias Jurídicas y Sociale

Efectos de la evicción producida

Cuando el reclamo del tercero tiene éxito, determina la privación total o parcial del derecho adquirido. Tal privación abre la etapa central y definitiva de la figura, esto es, la evicción producida. El efecto, cuando se dan los requisitos expuestos, es lo que tradicionalmente, en nuestro derecho, recibió la denominación de obligación de saneamiento. El contenido del dicha obligación puede abarcar la restitución del precio y la indemnización del dañó producido.Facultad de Ciencias Jurídicas y Sociale

Imaging mass cytometry and multiplatform genomics define the phenogenomic landscape of breast cancer

Genomic alterations shape cell phenotypes and the structure of tumor ecosystems in poorly defined ways. To investigate these relationships, we used imaging mass cytometry to quantify the expression of 37 proteins with subcellular spatial resolution in 483 tumors from the METABRIC cohort. Single-cell analysis revealed cell phenotypes spanning epithelial, stromal and immune types. Distinct combinations of cell phenotypes and cell–cell interactions were associated with genomic subtypes of breast cancer. Epithelial luminal cell phenotypes separated into those predominantly impacted by mutations and those affected by copy number aberrations. Several features of tumor ecosystems, including cellular neighborhoods, were linked to prognosis, illustrating their clinical relevance. In summary, systematic analysis of single-cell phenotypic and spatial correlates of genomic alterations in cancer revealed how genomes shape both the composition and architecture of breast tumor ecosystems and will enable greater understanding of the phenotypic impact of genomic alterations

Quantic Analysis of Formation of a Biomaterial of Latex, Retinol, and Chitosan for Biomedical Applications

The present work shows the quantum theoretical analysis and practical tests for the formation of a homogeneous mixture with Latex (Lx), Chitosan (Qn) and Retinol (Rl), which work as possible biomaterial for regeneration of epithelial tissue. Lx, Qn, and Rl compounds molecules were designed through Hyperchem to get the coefficient of electrostatic potential calculations. The amounts used to create the biomaterial are minimum depending on the quantities of molecules used in chemical design. A positive calculation was obtained for the reaction of these three compounds and the formation of the biomaterial in physical checking theory etc

Genome-driven integrated classification of breast cancer validated in over 7,500 samples

Abstract Background: IntClust is a classification of breast cancer comprising 10 subtypes based on molecular drivers identified through the integration of genomic and transcriptomic data from 1,000 breast tumors and validated in a further 1,000. We present a reliable method for subtyping breast tumors into the IntClust subtypes based on gene expression and demonstrate the clinical and biological validity of the IntClust classification. Results: We developed a gene expression-based approach for classifying breast tumors into the ten IntClust subtypes by using the ensemble profile of the index discovery dataset. We evaluate this approach in 983 independent samples for which the combined copy-number and gene expression IntClust classification was available. Only 24 samples are discordantly classified. Next, we compile a consolidated external dataset composed of a further 7,544 breast tumors. We use our approach to classify all samples into the IntClust subtypes. All ten subtypes are observable in most studies at comparable frequencies. The IntClust subtypes are significantly associated with relapse-free survival and recapitulate patterns of survival observed previously. In studies of neo-adjuvant chemotherapy, IntClust reveals distinct patterns of chemosensitivity. Finally, patterns of expression of genomic drivers reported by TCGA (The Cancer Genome Atlas) are better explained by IntClust as compared to the PAM50 classifier

DNA methylation landscapes of 1538 breast cancers reveal a replication-linked clock, epigenomic instability and cis-regulation.

DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, reduced representation bisulfite sequencing (RRBS) profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, this study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors

Improving Breast Cancer Survival Analysis through Competition-Based Multidimensional Modeling

Breast cancer is the most common malignancy in women and is responsible for hundreds of thousands of deaths annually. As with most cancers, it is a heterogeneous disease and different breast cancer subtypes are treated differently. Understanding the difference in prognosis for breast cancer based on its molecular and phenotypic features is one avenue for improving treatment by matching the proper treatment with molecular subtypes of the disease. In this work, we employed a competition-based approach to modeling breast cancer prognosis using large datasets containing genomic and clinical information and an online real-time leaderboard program used to speed feedback to the modeling team and to encourage each modeler to work towards achieving a higher ranked submission. We find that machine learning methods combined with molecular features selected based on expert prior knowledge can improve survival predictions compared to current best-in-class methodologies and that ensemble models trained across multiple user submissions systematically outperform individual models within the ensemble. We also find that model scores are highly consistent across multiple independent evaluations. This study serves as the pilot phase of a much larger competition open to the whole research community, with the goal of understanding general strategies for model optimization using clinical and molecular profiling data and providing an objective, transparent system for assessing prognostic models