Experimental evidence indicates that aging leads to accumulation of senescent cells in tissues and they develop a secretory phenotype (also known as SASP, for senescence-associated secretory phenotype) that can contribute to chronic inflammation and diseases. Recent results have showed that markers of senescence in astrocytes from aged brains are increased in brains with Alzheimer’s disease. These studies strongly involved the stress kinase p38MAPK in the regulation of the secretory phenotype of astrocytes, yet the molecular mechanisms underlying the onset of senescence and SASP activation remain unclear. In this work, we propose a discrete logical model for astrocyte senescence determined by the level of DNA damage (reparable or irreparable DNA strand breaks) where the kinase p38MAPK plays a central role in the regulation of senescence and SASP. The model produces four alternative stable states: proliferation, transient cycle arrest, apoptosis and senescence (and SASP) computed from its inputs representing DNA damages. Perturbations of the model were performed through gene gain or loss of functions and compared with results concerning cultures of normal and mutant astrocytes showing agreement in most cases. Moreover, the model allows some predictions that remain to be tested experimentally.

BackgroundDNA damage (single or double-strand breaks) triggers adapted cellular responses. These responses are elicited through signalling pathways, which activate cell cycle checkpoints and basically lead to three cellular fates: cycle arrest promoting DNA repair, senescence (permanent arrest) or cell death. Cellular senescence is known for having a tumour-suppressive function and its regulation arouses a growing scientific interest. Here, we advance a qualitative model covering DNA damage response pathways, focusing on G1/S checkpoint enforcement, supposedly more sensitive to arrest than G2/M checkpoint.ResultsWe define a discrete, logical model encompassing ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) pathways activation upon DNA damage, as well as G1/S checkpoint main components. It also includes the stress responsive protein p38MAPK (mitogen-activated protein kinase 14) known to be involved in the regulation of senescence. The model has four outcomes that convey alternative cell fates: proliferation, (transient) cell cycle arrest, apoptosis and senescence. Different levels of DNA damage are considered, defined by distinct combinations of single and double-strand breaks. Each leads to a single stable state denoting the cell fate adopted upon this specific damage. A range of model perturbations corresponding to gene loss-of-function or gain-of-function is compared to experimental mutations.ConclusionsAs a step towards an integrative model of DNA-damage response pathways to better cover the onset of senescence, our model focuses on G1/S checkpoint enforcement. This model qualitatively agrees with most experimental observations, including experiments involving mutations. Furthermore, it provides some predictions.

A recent model proposing that a barrier is raised against tumor evolution in pre-cancer tissues is investigated. For that we quantify expression alterations in genome maintenance pathways: DNA damage response, death pathways and cell cycle and also differentially expressed genes in transcriptomes of pre-cancerous and cancerous lesions deposited in the GEO database. We find that the main alterations in pre-cancer samples comprising the barrier are: (1) DNA double strand-breaks signaling and repair pathways induction, (2) upregulation of cyclin-dependent kinases, (3) p53 dependent (and independent) repair and apoptosis pathways induction and (4) replicative senescence induction early in tissue transformation. In the cancer samples we find that the induced pathways in pre-cancer are systematically inhibited and the only remaining induced pathway is p53, whereas the retinoblastoma pathway arises induced in most samples. The results give support to the model, furthermore they reveal the involvement of additional mechanisms in pre-cancer, including the early induction of replicative senescence and of p53 independent apoptosis.

Este trabalho busca compilar e testar atividades na área de ensino da matemática, com a participação ativa dos alunos, através de experimentos e experimentação, unindo diálogo à teoria como opção metodológica, ou seja, buscando inserir a matemática através de experiências ativas afim de reproduzir, em sala de aula, atividades que fazem parte do cotidiano dos alunos. Nesse sentido, fez-se a reflexão sobre a necessidade de tornar a matemática mais atraente, onde a sala de aula não seja um ambiente isolado, mas que proporcione um espaço de discussão para unir as teorias e as práticas com o objetivo de formar alunos ativos em seu processo de ensino e aprendizagem. Este modelo de atividade foi desenvolvido em uma escola privada na cidade de Rosário do Sul – RS, em uma turma do 9º ano do ensino fundamental, com 12 alunos, e realizado em quatro momentos distintos: introdução a conceitos iniciais, experimentação laboratorial, experimentação no mundo real com uso de aplicativo, e por fim,  realização de cálculos e discussão dos resultados. Ao término deste trabalho foi possível perceber que os alunos obtiveram ganhos significativos em sua aprendizagem, confirmando que é possível fazer matemática através de atividades práticas e com experiências lúdicas nos anos finais do ensino fundamental.