Boolean dynamics revisited through feedback interconnections

Boolean models of physical or biological systems describe the global dynamics of the system and their attractors typically represent asymptotic behaviors. In the case of large networks composed of several modules, it may be difficult to identify all the attractors. To explore Boolean dynamics from a novel viewpoint, we will analyse the dynamics emerging from the composition of two known Boolean modules. The state transition graphs and attractors for each of the modules can be combined to construct a new asymptotic graph which will (1) provide a reliable method for attractor computation with partial information; (2) illustrate the differences in dynamical behavior induced by the updating strategy (asynchronous, synchronous, or mixed); and (3) show the inherited organization/structure of the original network’s state transition graph.publishe

Control Strategy Identification via Trap Spaces in Boolean Networks

The control of biological systems presents interesting applications such as cell reprogramming or drug target identification. A common type of control strategy consists in a set of interventions that, by fixing the values of some variables, force the system to evolve to a desired state. This work presents a new approach for finding control strategies in biological systems modeled by Boolean networks. In this context, we explore the properties of trap spaces, subspaces of the state space which the dynamics cannot leave. Trap spaces for biological networks can often be efficiently computed, and provide useful approximations of attraction basins. Our approach provides control strategies for a target phenotype that are based on interventions that allow the control to be eventually released. Moreover, our method can incorporate information about the attractors to find new control strategies that would escape usual percolation-based methods. We show the applicability of our approach to two cell fate decision models.Comment: 16 pages, 2 figure

Mathematical Modeling of the \u3ci\u3eCandida albicans\u3c/i\u3e Yeast to Hyphal Transition Reveals Novel Control Strategies

Candida albicans, an opportunistic fungal pathogen, is a significant cause of human infections, particularly in immunocompromised individuals. Phenotypic plasticity between two morphological phenotypes, yeast and hyphae, is a key mechanism by which C. albicans can thrive in many microenvironments and cause disease in the host. Understanding the decision points and key driver genes controlling this important transition and how these genes respond to different environmental signals is critical to understanding how C. albicans causes infections in the host. Here we build and analyze a Boolean dynamical model of the C. albicans yeast to hyphal transition, integrating multiple environmental factors and regulatory mechanisms. We validate the model by a systematic comparison to prior experiments, which led to agreement in 17 out of 22 cases. The discrepancies motivate alternative hypotheses that are testable by follow-up experiments. Analysis of this model revealed two time-constrained windows of opportunity that must be met for the complete transition from the yeast to hyphal phenotype, as well as control strategies that can robustly prevent this transition. We experimentally validate two of these control predictions in C. albicans strains lacking the transcription factor UME6 and the histone deacetylase HDA1, respectively. This model will serve as a strong base from which to develop a systems biology understanding of C. albicans morphogenesis

Mathematical modeling of the Candida albicans yeast to hyphal transition reveals novel control strategies.

Candida albicans, an opportunistic fungal pathogen, is a significant cause of human infections, particularly in immunocompromised individuals. Phenotypic plasticity between two morphological phenotypes, yeast and hyphae, is a key mechanism by which C. albicans can thrive in many microenvironments and cause disease in the host. Understanding the decision points and key driver genes controlling this important transition and how these genes respond to different environmental signals is critical to understanding how C. albicans causes infections in the host. Here we build and analyze a Boolean dynamical model of the C. albicans yeast to hyphal transition, integrating multiple environmental factors and regulatory mechanisms. We validate the model by a systematic comparison to prior experiments, which led to agreement in 17 out of 22 cases. The discrepancies motivate alternative hypotheses that are testable by follow-up experiments. Analysis of this model revealed two time-constrained windows of opportunity that must be met for the complete transition from the yeast to hyphal phenotype, as well as control strategies that can robustly prevent this transition. We experimentally validate two of these control predictions in C. albicans strains lacking the transcription factor UME6 and the histone deacetylase HDA1, respectively. This model will serve as a strong base from which to develop a systems biology understanding of C. albicans morphogenesis

Synthesis and Simulation of Ensembles of Boolean Networks for Cell Fate Decision

International audienceThe construction of models of biological networks from prior knowledge and experimental data often leads to a multitude of candidate models. Devising a single model from them can require arbitrary choices, which may lead to strong biases in subsequent predictions. We introduce here a methodology for a) synthesizing Boolean model ensembles satisfying a set of biologically relevant constraints and b) reasoning on the dynamics of the ensembles of models. The synthesis is performed using Answer-Set Programming, extending prior work to account for solution diversity and universal constraints on reachable fixed points, enabling an accurate specification of desired dynamics. The sampled models are then simulated and the results are aggregated through averaging or can be analyzed as a multi-dimensional distribution. We illustrate our approach on a previously published Boolean model of a molecular network regulating the cell fate decisions in cancer progression. It appears that the ensemble-based approach to Boolean modelling brings new insights on the variability of synergistic interacting mutations effect concerning propensity of a cancer cell to metastasize

Comparative results between hysteroscopic and transvaginal ultrasonographic findings in public service

Objective: To evaluate findings of transvaginal ultrasonography and video hysteroscopies in women from a reference center in Aracaju-SE, comparing the results among themselves and as biopsies performed. Method: Retrospective observational study with 361 women aged 20 to 81 years submitted to diagnostic hysteroscopy and ultrasonography, attended at the Center for Integral Attention to Women's Health (CAISM), where the age, origin, indication of hysteroscopy, ultrasonographic diagnosis, hysteroscopic and histopathological. Results: The studied population of 361 patients with average age of 46.61 years and standard deviation of 11.8. The most frequent ultrasonographic and hysteroscopic findings were for endometrial polyp with 50.69% (183) and 47.09% (170), respectively. Biopsies were performed in 250 patients, with 42.8% of them being the most frequent endometrial polyp (107). Among ultrasonographic and hysteroscopic findings, there was a significant association for the diagnosis of endometrial polyp (p-0.001), endometrial thickening (p-0.001) and submucous myoma (p-0.001). Comparing anatomopathological and hysteroscopic findings, there was a significant association between submucosal myoma and endometrial polyp (p-0.002 and p-0.001, respectively). There was no significant association for the diagnosis of endometrial thickening (p-0.382) and submucosal myoma (p-0.075) when comparing biopsies and ultrasonography, but seen for endometrial polyp (p-0.049). Conclusion: A main indication for hysteroscopy and the main result of anatomopathological examination for endometrial polyp. There was a significant association for the results of polyp, endometrial thickening and myoma when comparing hysteroscopy and ultrasonography, and in the comparison between this examination and biopsy there is only a significant association for polyp.Objetivo: Avaliar achados de ultrassonografia transvaginal e vídeo histeroscopias em mulheres oriundas de um centro de referência em Aracaju-SE, comparando os resultados entre si e com as biópsias realizadas. Método: Estudo observacional de caráter retrospectivo com 361 mulheres de 20 a 81 anos, submetidas à histeroscopia diagnóstica e ultrassonografia, atendidas no Centro de Atenção Integral a Saúde da Mulher (CAISM) onde avaliou-se idade, procedência, indicação da histeroscopia, diagnóstico ultrassonográfico, histeroscópico e histopatológico. Resultado: A população estudada foi de 361 pacientes com média de idade de 46,61 anos e desvio padrão de 11,8. O achado ultrassonográfico e histeroscópico mais frequentes foi pólipo endometrial com 50,69% (183) e 47,09% (170), respectivamente. Foram realizadas biópsias em 250 pacientes, tendo como achado mais frequente pólipo endometrial 42,80% (107). Entre os achados ultrassonográficos e histeroscópicos houve associação significativa para o diagnóstico de pólipo endometrial (p-0,001), espessamento endometrial (p-0,001) e mioma submucoso (p-0,001). Comparando-se os achados anatomopatológicos e histeroscópicos houve associação significativa para mioma submucoso e pólipo endometrial (p-0,002 e p-0,001, respectivamente). Não houve associação significativa para o diagnóstico de espessamento endometrial (p-0,382) e mioma submucoso (p-0,075) ao comparar-se biópsias e ultrassonografias, mas houve para pólipo endometrial (p-0,049). Conclusão: A principal indicação para histeroscopia e o principal resultado do exame anatomopatológico foi pólipo endometrial. Houve associação significativa para os resultados de pólipo, espessamento endometrial e mioma quando comparadas histeroscopia e ultrassonografia, sendo que na comparação entre este exame e biópsia só houve associação significativa para pólipo.Aracaju, S