Browsing by Author "Cerda, Mauricio"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    A computational framework for testing hypotheses of the minimal mechanical requirements for cell aggregation using early annual killifish embryogenesis as a model
    (FRONTIERS MEDIA SA, 2023) Montenegro-Rojas, Ignacio; Yanez, Guillermo; Skog, Emily; Guerrero-Calvo, Oscar; Andaur-Lobos, Martin; Dolfi, Luca; Cellerino, Alessandro; Cerda, Mauricio; Concha, Miguel L.; Bertocchi, Cristina; Rojas, Nicolas O.; Ravasio, Andrea; Rudge, Timothy J.
    Introduction: Deciphering the biological and physical requirements for the outset of multicellularity is limited to few experimental models. The early embryonic development of annual killifish represents an almost unique opportunity to investigate de novo cellular aggregation in a vertebrate model. As an adaptation to seasonal drought, annual killifish employs a unique developmental pattern in which embryogenesis occurs only after undifferentiated embryonic cells have completed epiboly and dispersed in low density on the egg surface. Therefore, the first stage of embryogenesis requires the congregation of embryonic cells at one pole of the egg to form a single aggregate that later gives rise to the embryo proper. This unique process presents an opportunity to dissect the self-organizing principles involved in early organization of embryonic stem cells. Indeed, the physical and biological processes required to form the aggregate of embryonic cells are currently unknown., Methods: Here, we developed an in silico, agent-based biophysical model that allows testing how cell-specific and environmental properties could determine the aggregation dynamics of early Killifish embryogenesis. In a forward engineering approach, we then proceeded to test two hypotheses for cell aggregation (cell-autonomous and a simple taxis model) as a proof of concept of modeling feasibility. In a first approach (cell autonomous system), we considered how intrinsic biophysical properties of the cells such as motility, polarity, density, and the interplay between cell adhesion and contact inhibition of locomotion drive cell aggregation into self-organized clusters. Second, we included guidance of cell migration through a simple taxis mechanism to resemble the activity of an organizing center found in several developmental models., Results: Our numerical simulations showed that random migration combined with low cell-cell adhesion is sufficient to maintain cells in dispersion and that aggregation can indeed arise spontaneously under a limited set of conditions, but, without environmental guidance, the dynamics and resulting structures do not recapitulate in vivo observations., Discussion: Thus, an environmental guidance cue seems to be required for correct execution of early aggregation in early killifish development. However, the nature of this cue (e.g., chemical or mechanical) can only be determined experimentally. Our model provides a predictive tool that could be used to better characterize the process and, importantly, to design informed experimental strategies.
  • Thumbnail Image
    Item
    Palmitic acid control of ciliogenesis modulates insulin signaling in hypothalamic neurons through an autophagy-dependent mechanism
    (SPRINGERNATURE, 2022) Avalos, Yenniffer; Paz Hernandez-Caceres, Maria; Lagos, Pablo; Pinto-Nunez, Daniela; Rivera, Patricia; Burgos, Paulina; Diaz-Castro, Francisco; Joy-Immediato, Michelle; Venegas-Zamora, Leslye; Lopez-Gallardo, Erik; Kretschmar, Catalina; Batista-Gonzalez, Ana; Cifuentes-Araneda, Flavia; Toledo-Valenzuela, Lilian; Rodriguez-Pena, Marcelo; Espinoza-Caicedo, Jasson; Perez-Leighton, Claudio; Bertocchi, Cristina; Cerda, Mauricio; Troncoso, Rodrigo; Parra, Valentina; Budini, Mauricio; Burgos, Patricia, V; Criollo, Alfredo; Morselli, Eugenia
    Palmitic acid (PA) is significantly increased in the hypothalamus of mice, when fed chronically with a high-fat diet (HFD). PA impairs insulin signaling in hypothalamic neurons, by a mechanism dependent on autophagy, a process of lysosomal-mediated degradation of cytoplasmic material. In addition, previous work shows a crosstalk between autophagy and the primary cilium (hereafter cilium), an antenna-like structure on the cell surface that acts as a signaling platform for the cell. Ciliopathies, human diseases characterized by cilia dysfunction, manifest, type 2 diabetes, among other features, suggesting a role of the cilium in insulin signaling. Cilium depletion in hypothalamic pro-opiomelanocortin (POMC) neurons triggers obesity and insulin resistance in mice, the same phenotype as mice deficient in autophagy in POMC neurons. Here we investigated the effect of chronic consumption of HFD on cilia; and our results indicate that chronic feeding with HFD reduces the percentage of cilia in hypothalamic POMC neurons. This effect may be due to an increased amount of PA, as treatment with this saturated fatty acid in vitro reduces the percentage of ciliated cells and cilia length in hypothalamic neurons. Importantly, the same effect of cilia depletion was obtained following chemical and genetic inhibition of autophagy, indicating autophagy is required for ciliogenesis. We further demonstrate a role for the cilium in insulin sensitivity, as cilium loss in hypothalamic neuronal cells disrupts insulin signaling and insulin-dependent glucose uptake, an effect that correlates with the ciliary localization of the insulin receptor (IR). Consistently, increased percentage of ciliated hypothalamic neuronal cells promotes insulin signaling, even when cells are exposed to PA. Altogether, our results indicate that, in hypothalamic neurons, impairment of autophagy, either by PA exposure, chemical or genetic manipulation, cause cilia loss that impairs insulin sensitivity.
  • Thumbnail Image
    Item
    Socioeconomic, Clinical, and Molecular Features of Breast Cancer Influence Overall Survival of Latin American Women
    (2022) de Almeida, Liz Maria; Cortés Arancibia, Sandra; Vilensky, Marta; Valenzuela, Olivia; Cortes-Sanabria, Laura; de Souza, Mirian; Alonso Barbeito, Rafael; Abdelhay, Eliana; Artagaveytia, Nora; Daneri-Navarro, Adrian; Llera, Andrea S.; Muller, Bettina; Podhajcer, Osvaldo L.; Velazquez, Carlos; Alcoba, Elsa; Alonso, Isabel; Bravo, Alicia, I; Camejo, Natalia; Maria Carraro, Dirce; Castro, Monica; Cataldi, Sandra; Cayota, Alfonso; Cerda, Mauricio; Colombo, Alicia; Crocamo, Susanne; Del Toro-Arreola, Alicia; Delgadillo-Cristerna, Raul; Delgado, Lucia; Breitenbach, Marisa Dreyer; Fernandez, Elmer; Fernandez, Jorge; Fernandez, Wanda; Franco-Topete, Ramon A.; Gaete, Fancy; Gomez, Jorge; Gonzalez-Ramirez, Leivy P.; Guerrero, Marisol; Gutierrez-Rubio, Susan A.; Jalfin, Beatriz; Lopez-Vazquez, Alejandra; Loria, Dora; Miguez, Silvia; Moran-Mendoza, Andres de J.; Morgan-Villela, Gilberto; Mussetti, Carina; Nagai, Maria Aparecida; Oceguera-Villanueva, Antonio; Reis, Rui M.; Retamales, Javier; Rodriguez, Robinson; Rosales, Cristina; Salas-Gonzalez, Efrain; Segovia, Laura; Sendoya, Juan M.; Silva-Garcia, Aida A.; Vina, Stella; Zagame, Livia; Jones, Beth; Szklo, Moyses
    Molecular profile of breast cancer in Latin-American women was studied in five countries: Argentina, Brazil, Chile, Mexico, and Uruguay. Data about socioeconomic characteristics, risk factors, prognostic factors, and molecular subtypes were described, and the 60-month overall cumulative survival probabilities (OS) were estimated. From 2011 to 2013, 1,300 eligible Latin-American women 18 years or older, with a diagnosis of breast cancer in clinical stage II or III, and performance status not less than or equal to 1 were invited to participate in a prospective cohort study. Face-to-face interviews were conducted, and clinical and outcome data, including death, were extracted from medical records. Unadjusted associations were evaluated by Chi-squared and Fisher's exact tests and the OS by Kaplan-Meier method. Log-rank test was used to determine differences between cumulative probability curves. Multivariable adjustment was carried out by entering potential confounders in the Cox regression model. The OS at 60 months was 83.9%. Multivariable-adjusted death hazard differences were found for women living in Argentina (2.27), Chile (1.95), and Uruguay (2.42) compared with Mexican women, for older (>= 60 years) (1.84) compared with younger (<= 40 years) women, for basal-like subtype (5.8), luminal B (2.43), and HER2-enriched (2.52) compared with luminal A subtype, and for tumor clinical stages IIB (1.91), IIIA (3.54), and IIIB (3.94) compared with stage IIA women. OS was associated with country of residence, PAM50 intrinsic subtype, age, and tumor stage at diagnosis. While the latter is known to be influenced by access to care, including cancer screening, timely diagnosis and treatment, including access to more effective treatment protocols, it may also influence epigenetic changes that, potentially, impact molecular subtypes. Data derived from heretofore understudied populations with unique geographic ancestry and sociocultural experiences are critical to furthering our understanding of this complexity.
  • Thumbnail Image
    Item
    VolumePeeler: a novel FIJI plugin for geometric tissue peeling to improve visualization and quantification of 3D image stacks
    (BMC, 2023) Gatica, Marilyn; Navarro, Carlos F. F.; Lavado, Alejandro; Reig, German; Pulgar, Eduardo; Llanos, Paula; Haertel, Steffen; Ravasio, Andrea; Bertocchi, Cristina; Concha, Miguel L. L.; Cerda, Mauricio
    Motivation Quantitative descriptions of multi-cellular structures from optical microscopy imaging are prime to understand the variety of three-dimensional (3D) shapes in living organisms. Experimental models of vertebrates, invertebrates and plants, such as zebrafish, killifish, Drosophila or Marchantia, mainly comprise multilayer tissues, and even if microscopes can reach the needed depth, their geometry hinders the selection and subsequent analysis of the optical volumes of interest. Computational tools to "peel" tissues by removing specific layers and reducing 3D volume into planar images, can critically improve visualization and analysis.Results We developed VolumePeeler, a versatile FIJI plugin for virtual 3D "peeling" of image stacks. The plugin implements spherical and spline surface projections. We applied VolumePeeler to perform peeling in 3D images of spherical embryos, as well as non-spherical tissue layers. The produced images improve the 3D volume visualization and enable analysis and quantification of geometrically challenging microscopy datasets.