Genome-wide multi-parametric analysis of H2AX or γH2AX distributions during ionizing radiation-induced DNA damage response

Background: After induction of DNA double strand breaks (DSBs), the DNA damage response (DDR) is activated. One of the earliest events in DDR is the phosphorylation of serine 139 on the histone variant H2AX (gH2AX) catalyzed by phosphatidylinositol 3-kinases-related kinases. Despite being extensively studied, H2AX distribution[1] across the genome and gH2AX spreading around DSBs sites[2] in the context of different chromatin compaction states or transcription are yet to be fully elucidated. Materials and methods: gH2AX was induced in human hepatocellular carcinoma cells (HepG2) by exposure to 10 Gy X-rays (250 kV, 16 mA). Samples were incubated 0.5, 3 or 24 hours post irradiation to investigate early, intermediate and late stages of DDR, respectively. Chromatin immunoprecipitation was performed to select H2AX, H3 and gH2AX-enriched chromatin fractions. Chromatin-associated DNA was then sequenced by Illumina ChIP-Seq platform. HepG2 gene expression and histone modification (H3K36me3, H3K9me3) ChIP-Seq profiles were retrieved from Gene Expression Omnibus (accession numbers GSE30240 and GSE26386, respectively). Results: First, we combined G/C usage, gene content, gene expression or histone modification profiles (H3K36me3, H3K9me3) to define genomic compartments characterized by different chromatin compaction states or transcriptional activity. Next, we investigated H3, H2AX and gH2AX distributions in such defined compartments before and after exposure to ionizing radiation (IR) to study DNA repair kinetics during DDR. Our sequencing results indicate that H2AX distribution followed H3 occupancy and, thus, the nucleosome pattern. The highest H2AX and H3 enrichment was observed in transcriptionally active compartments (euchromatin) while the lowest was found in low G/C and gene-poor compartments (heterochromatin). Under physiological conditions, the body of highly and moderately transcribed genes was devoid of gH2AX, despite presenting high H2AX levels. gH2AX accumulation was observed in 5’ or 3’ flanking regions, instead. The same genes showed a prompt gH2AX accumulation during the early stage of DDR which then decreased over time as DDR proceeded. Finally, during the late stage of DDR the residual gH2AX signal was entirely retained in heterochromatic compartments. At this stage, euchromatic compartments were completely devoid of gH2AX despite presenting high levels of non-phosphorylated H2AX. Conclusions: We show that gH2AX distribution ultimately depends on H2AX occupancy, the latter following H3 occupancy and, thus, nucleosome pattern. Both H2AX and H3 levels were higher in actively transcribed compartments. However, gH2AX levels were remarkably low over the body of actively transcribed genes suggesting that transcription levels antagonize gH2AX spreading. Moreover, repair processes did not take place uniformly across the genome; rather, DNA repair was affected by genomic location and transcriptional activity. We propose that higher H2AX density in euchromaticcompartments results in high relative gH2AXconcentration soon after the activation of DDR, thus favoring the recruitment of the DNA repair machinery to those compartments. When the damage is repaired and gH2AX is removed, its residual fraction is retained in the heterochromatic compartments which are then targeted and repaired at later times

On the X-rank with respect to linear projections of projective varieties

In this paper we improve the known bound for the $X$-rank $R_{X}(P)$ of an element $P\in {\mathbb{P}}^N$ in the case in which $X\subset {\mathbb P}^n$ is a projective variety obtained as a linear projection from a general $v$-dimensional subspace $V\subset {\mathbb P}^{n+v}$. Then, if $X\subset {\mathbb P}^n$ is a curve obtained from a projection of a rational normal curve $C\subset {\mathbb P}^{n+1}$ from a point $O\subset {\mathbb P}^{n+1}$, we are able to describe the precise value of the $X$-rank for those points $P\in {\mathbb P}^n$ such that $R_{X}(P)\leq R_{C}(O)-1$ and to improve the general result. Moreover we give a stratification, via the $X$-rank, of the osculating spaces to projective cuspidal projective curves $X$. Finally we give a description and a new bound of the $X$-rank of subspaces both in the general case and with respect to integral non-degenerate projective curves.Comment: 10 page

Uncertainty in multitask learning: joint representations for probabilistic MR-only radiotherapy planning

Multi-task neural network architectures provide a mechanism that jointly integrates information from distinct sources. It is ideal in the context of MR-only radiotherapy planning as it can jointly regress a synthetic CT (synCT) scan and segment organs-at-risk (OAR) from MRI. We propose a probabilistic multi-task network that estimates: 1) intrinsic uncertainty through a heteroscedastic noise model for spatially-adaptive task loss weighting and 2) parameter uncertainty through approximate Bayesian inference. This allows sampling of multiple segmentations and synCTs that share their network representation. We test our model on prostate cancer scans and show that it produces more accurate and consistent synCTs with a better estimation in the variance of the errors, state of the art results in OAR segmentation and a methodology for quality assurance in radiotherapy treatment planning.Comment: Early-accept at MICCAI 2018, 8 pages, 4 figure

Aplicación de un sistema conversacional en el canal de Facebook usando procesamiento de lenguaje natural para la empresa pleromadabar durante la temporada 2020 a 2021

La razón del desarrollo de esta tesis es dar a conocer el proceso de aplicación y las etapas por las que se tuvieron que cursar, sobre el sistema conversacional de entrega de información en el canal de Facebook Messenger usando procesamiento de lenguaje natural para la empresa PleromaDabar. Para la creación de esta tesis se ha hecho uso de los conocimientos y habilidades obtenidos durante los ciclos de estudios de la carrera profesional de Ingeniería de Computación y Sistemas, a esto se le ha añadido el tiempo de experiencia laboral, networking profesional, así como otros conocimientos propios adquirido a través del tiempo. Se inicia el informe brindando información sobre el equipo de investigación que es autor de esta tesis, así como la definición de las etapas, la estimación de costos y tiempo a invertir en la presente investigación. La segunda parte, brinda información acerca de la problemática, objetivos y justificación de la investigación a realizar. La tercera parte, detalla estudios previos que se han realizado sobre el tema en estudio, así como la definición de la hipótesis junto con sus variables e indicadores, de esta investigación. Añadido a esto se detalla la población y muestra de estudio asó como el diseño, técnicas e instrumentos de investigación. La cuarta parte, detalla los aspectos a considerar sobre la empresa a la cual se le ha de aplicar la investigación. Además de la definición de tecnologías y plataformas, despliegue del sistema conversacional. Finalmente hacemos presentación de los resultados obtenidos, las cuales se detallan en la contrastación de la hipótesis de acuerdo a cada una de las variables determinadas previamente. Adicionalmente se trata la discusión de los resultados y conclusiones, extraídas de la aplicación de la presente investigaciónThe reason for the development of this thesis is to demonstrate the process of implementation and the stages that had to be taken, about the conversational system for information delivery through the Facebook Messenger channel using natural language processing for the company Pleroma Dabar. For the creation of this thesis, we have made use of the knowledge and skills obtained during the study cycles of the professional career of Computer and Systems Engineering, to this it has been added the time of work experience, professional networking, as well as other fields of knowledge acquired over time. The report begins by providing information about the research team that is author of this thesis, as well as the definition of the stages, the estimated costs and time to be invested in this research. The second part provides information about the problems, objectives and justification of the research to be carried out. The third part details previous studies that have been carried out on the subject under study, as well as the definition of the hypothesis together with its variables and indicators, of this research. In addition to this, the study population and sample are detailed, as well as the research design, techniques and instruments. The fourth part details the aspects to be considered about the company to which the research is to be applied. In addition we define the technologies, platforms and deployment of the conversational system. Finally, we present the obtained results, which are detailed in the testing of the hypothesis according to each of the variables previously determined. Additionally, we discuss the results and conclusions drawn from the application of this research.Tesi