Improving automation in model-driven engineering using examples

Cette thèse a pour but d’améliorer l’automatisation dans l’ingénierie dirigée par les modèles (MDE pour Model Driven Engineering). MDE est un paradigme qui promet de réduire la complexité du logiciel par l’utilisation intensive de modèles et des transformations automatiques entre modèles (TM). D’une façon simplifiée, dans la vision du MDE, les spécialistes utilisent plusieurs modèles pour représenter un logiciel, et ils produisent le code source en transformant automatiquement ces modèles. Conséquemment, l’automatisation est un facteur clé et un principe fondateur de MDE. En plus des TM, d’autres activités ont besoin d’automatisation, e.g. la définition des langages de modélisation et la migration de logiciels. Dans ce contexte, la contribution principale de cette thèse est de proposer une approche générale pour améliorer l’automatisation du MDE. Notre approche est basée sur la recherche méta-heuristique guidée par les exemples. Nous appliquons cette approche sur deux problèmes importants de MDE, (1) la transformation des modèles et (2) la définition précise de langages de modélisation. Pour le premier problème, nous distinguons entre la transformation dans le contexte de la migration et les transformations générales entre modèles. Dans le cas de la migration, nous proposons une méthode de regroupement logiciel (Software Clustering) basée sur une méta-heuristique guidée par des exemples de regroupement. De la même façon, pour les transformations générales, nous apprenons des transformations entre modèles en utilisant un algorithme de programmation génétique qui s’inspire des exemples des transformations passées. Pour la définition précise de langages de modélisation, nous proposons une méthode basée sur une recherche méta-heuristique, qui dérive des règles de bonne formation pour les méta-modèles, avec l’objectif de bien discriminer entre modèles valides et invalides. Les études empiriques que nous avons menées, montrent que les approches proposées obtiennent des bons résultats tant quantitatifs que qualitatifs. Ceux-ci nous permettent de conclure que l’amélioration de l’automatisation du MDE en utilisant des méthodes de recherche méta-heuristique et des exemples peut contribuer à l’adoption plus large de MDE dans l’industrie à là venir.This thesis aims to improve automation in Model Driven Engineering (MDE). MDE is a paradigm that promises to reduce software complexity by the mean of the intensive use of models and automatic model transformation (MT). Roughly speaking, in MDE vision, stakeholders use several models to represent the software, and produce source code by automatically transforming these models. Consequently, automation is a key factor and founding principle of MDE. In addition to MT, other MDE activities require automation, e.g. modeling language definition and software migration. In this context, the main contribution of this thesis is proposing a general approach for improving automation in MDE. Our approach is based on meta-heuristic search guided by examples. We apply our approach to two important MDE problems, (1) model transformation and (2) precise modeling languages. For transformations, we distinguish between transformations in the context of migration and general model transformations. In the case of migration, we propose a software clustering method based on a search algorithm guided by cluster examples. Similarly, for general transformations, we learn model transformations by a genetic programming algorithm taking inspiration from examples of past transformations. For the problem of precise metamodeling, we propose a meta-heuristic search method to derive well-formedness rules for metamodels with the objective of discriminating examples of valid and invalid models. Our empirical evaluation shows that the proposed approaches exhibit good results. These allow us to conclude that improving automation in MDE using meta-heuristic search and examples can contribute to a wider adoption of MDE in industry in the coming years

Identification of novel transcripts with differential dorso-ventral expression in Xenopus gastrula using serial analysis of gene expression

Comparison of dorsal and ventral transcriptomes of Xenopus tropicalis gastrulae using serial analysis of gene expression provides at least 86 novel differentially expressed transcripts

Aging and oral squamous cell carcinoma development: the role of cellular senescence

The gradual accumulation and inadequate renewal of senescent cells over time drive organismal aging. Senescent cells undergo altered gene expression and release inflammatory mediators collectively termed the senescence-associated secretory phenotype (SASP), which significantly contributes to a spectrum of age-related disorders, including cancer. In the context of carcinogenesis, the SASP produced by senescent cells has been implicated in the promotion of epithelial cancers, including oral squamous cell carcinoma (OSCC), the most common form of oral cancer. Senescent cells within the tumor microenvironment release factors that amplify the growth and invasiveness of neighboring cancer cells. Senotherapeutics, including senolytics and senomorphics, emerge as promising modalities to target senescent cells and their associated inflammatory factors, thereby opening novel avenues for augmenting the efficacy of cancer treatments. Here, we review the general aspects of cellular senescence, focusing on the relation between senescence-related inflammation with cancer development. We also analyze the available evidence linking cellular senescence with OSCC, highlighting possible clinical applications

Cambios en la tendencia de mortalidad por suicidio en Chile, 1997-2018

Using information from the mortality database at Chile’s Department of Statistics and Health Information (Ministry of Health), an ecological time-series study was conducted to determine changing trends in suicide rates by sex and age group in Chile from 1997 to 2018. Results show that the mortality rate for men in 2018 was 20.1 per 100,000, almost five times higher than the rate for women. Trends in both sexes show a decrease in aver-age annual percent change of -5.4% [CI95% (-12.9; 1.9)] between 2009 and 2013. Over the same period, the average annual percent change for men was -5.8% [CI95% (-12.5; 2.3)], while for women it was -4.0 [CI95% (-5.8; -2.2)] between 2008 and 2018. No changes have been observed in trends for men aged 60 and over, the group with the high-est rates. Although suicide rates declined following the implementation of policies focus-ing on risk factors for suicide, it is necessary to evaluate the implementation of these pol-icies and devise similar actions geared toward populations with greater risk of suicide.Con base en el registro de defunciones del Departamento de Estadísticas e Información del Ministerio de Salud de Chile, se realizó un estudio ecológico de series de tiempo para determinar cambios en la tendencia de las tasas de mortalidad por suicidio en Chile según sexo y edad, en el periodo 1997-2018. Los resultados muestran que la tasa de mortalidad en hombres para el año 2018 fue de 20,1 por 100.000, siendo casi 5 veces más que la de mujeres. La tendencia en ambos sexos muestra un descenso en el porcentaje de cambio anual del -5,4% [IC95% (-12,9; 1,9)] en el periodo 2009-2013. Los hombres, en el mismo periodo, muestran un porcentaje de cambio anual del -5,8% [IC95% (-12,5; 2,3)], mientras que en las mujeres, para el periodo 2008- 2018, es -4,0% [IC95% (-5,8; -2,2)]. No se observaron cambios en la tendencia en los hombres de 60 o más años, siendo este grupo el que presenta las tasas más altas. Si bien esta disminución se registra con posterioridad a la implementación de políticas enfocadas en factores de riesgo de suicidio, es necesario evaluar sistemáticamente dichas políticas e implementar otras con enfoque en las poblaciones identificadas con mayor riesgo

Expression of Transposable Elements in Neural Tissues during Xenopus Development

Transposable elements comprise a large proportion of animal genomes. Transposons can have detrimental effects on genome stability but also offer positive roles for genome evolution and gene expression regulation. Proper balance of the positive and deleterious effects of transposons is crucial for cell homeostasis and requires a mechanism that tightly regulates their expression. Herein we describe the expression of DNA transposons of the Tc1/mariner superfamily during Xenopus development. Sense and antisense transcripts containing complete Tc1-2_Xt were detected in Xenopus embryos. Both transcripts were found in zygotic stages and were mainly localized in Spemann's organizer and neural tissues. In addition, the Tc1-like elements Eagle, Froggy, Jumpy, Maya, Xeminos and TXr were also expressed in zygotic stages but not oocytes in X. tropicalis. Interestingly, although Tc1-2_Xt transcripts were not detected in Xenopus laevis embryos, transcripts from other two Tc1-like elements (TXr and TXz) presented a similar temporal and spatial pattern during X. laevis development. Deep sequencing analysis of Xenopus tropicalis gastrulae showed that PIWI-interacting RNAs (piRNAs) are specifically derived from several Tc1-like elements. The localized expression of Tc1-like elements in neural tissues suggests that they could play a role during the development of the Xenopus nervous system

Temporal Perturbation of the Wnt Signaling Pathway in the Control of Cell Reprogramming Is Modulated by TCFI

Cyclic activation of the Wnt/β-catenin signaling pathway controls cell fusion-mediated somatic cell reprogramming. TCFs belong to a family of transcription factors that, in complex with β-catenin, bind and transcriptionally regulate Wnt target genes. Here, we show that Wnt/β-catenin signaling needs to be off during the early reprogramming phases of mouse embryonic fibroblasts (MEFs) into iPSCs. In MEFs undergoing reprogramming, senescence genes are repressed and mesenchymal-to-epithelial transition is favored. This is correlated with a repressive activity of TCF1, which contributes to the silencing of Wnt/β-catenin signaling at the onset of reprogramming. In contrast, the Wnt pathway needs to be active in the late reprogramming phases to achieve successful reprogramming. In conclusion, continued activation or inhibition of the Wnt/β-catenin signaling pathway is detrimental to the reprogramming of MEFs; instead, temporal perturbation of the pathway is essential for efficient reprogramming, and the "Wnt-off" state can be considered an early reprogramming marker.status: publishe

N-cadherin stabilises neural identity by dampening anti-neural signals

A switch from E- to N-cadherin regulates the transition from pluripotency to neural identity, but the mechanism by which cadherins regulate differentiation was previously unknown. Here, we show that the acquisition of N-cadherin stabilises neural identity by dampening anti-neural signals. We use quantitative image analysis to show that N-cadherin promotes neural differentiation independently of its effects on cell cohesiveness. We reveal that cadherin switching diminishes the level of nuclear beta-catenin, and that N-cadherin also dampens FGF activity and consequently stabilises neural fate. Finally, we compare the timing of cadherin switching and differentiation in vivo and in vitro, and find that this process becomes dysregulated during in vitro differentiation. We propose that N-cadherin helps to propagate a stable neural identity throughout the emerging neuroepithelium, and that dysregulation of this process contributes to asynchronous differentiation in culture

Distinct Wnt-driven primitive streak-like populations reflect in vivo lineage precursors

During gastrulation, epiblast cells are pluripotent and their fate is thought to be constrained principally by their position. Cell fate is progressively restricted by localised signalling cues from areas including the primitive streak. However, it is unknown whether this restriction accompanies, at the individual cell level, a reduction in potency. Investigation of these early transition events in vitro is possible via the use of epiblast stem cells (EpiSCs), self-renewing pluripotent cell lines equivalent to the postimplantation epiblast. Strikingly, mouse EpiSCs express gastrulation stage regional markers in self-renewing conditions. Here, we examined the differentiation potential of cells expressing such lineage markers. We show that undifferentiated EpiSC cultures contain a major subfraction of cells with reversible early primitive streak characteristics, which is mutually exclusive to a neural-like fraction. Using in vitro differentiation assays and embryo grafting we demonstrate that primitive streak-like EpiSCs are biased towards mesoderm and endoderm fates while retaining pluripotency. The acquisition of primitive streak characteristics by self-renewing EpiSCs is mediated by endogenous Wnt signalling. Elevation of Wnt activity promotes restriction towards primitive streak-associated lineages with mesendodermal and neuromesodermal characteristics. Collectively, our data suggest that EpiSC pluripotency encompasses a range of reversible lineage-biased states reflecting the birth of pioneer lineage precursors from a pool of uncommitted EpiSCs similar to the earliest cell fate restriction events taking place in the gastrula stage epiblast