Promoters architecture-based mechanism for noise-induced oscillations in a single-gene circuit

It is well known that single-gene circuits with negative feedback loop can lead to oscillatory gene expression when they operate with time delay. In order to generate these oscillations many processes can contribute to properly timing such delay. Here we show that the time delay coming from the transitions between internal states of the cis-regulatory system (CRS) can drive sustained oscillations in an auto-repressive single-gene circuit operating in a small volume like a cell. We found that the cooperative binding of repressor molecules is not mandatory for a oscillatory behavior if there are enough binding sites in the CRS. These oscillations depend on an adequate balance between the CRS kinetic, and the synthesis/ degradation rates of repressor molecules. This finding suggest that the multi-site CRS architecture can play a key role for oscillatory behavior of gene expression. Finally, our results can also help to synthetic biologists on the design of the promoters architecture for new genetic oscillatory circuits.Instituto de Física de Líquidos y Sistemas BiológicosFacultad de Ciencias ExactasCentro Regional de Estudios Genómico

¿Qué dicen los modelos matemáticos sobre el efecto de las medidas no farmacológicas de cuidado implementadas durante la pandemia por COVID-19 sobre otras enfermedades respiratorias?

INTRODUCTION: Mathematical models of infectious disease transmission allow to study different mechanisms which affect the temporal behavior. This work analyzed the impact of the decrease in transmissibility, as a result of measures of personal care adopted to reduce circulation of COVID-19, on the dynamics of influenza and respiratory syncytial virus (RSV). METHODS: A deterministic SIRS (susceptible-infected-recovered-susceptible) model with seasonal modulation was used to represent two diseases with short-term immunity and annual cycle: influenza and RSV. Changes in disease transmissibility were modeled by reducing it for two years and analyzing different scenarios. RESULTS: In this model, transmissibility reduction brings changes which sustain in the following years: very pronounced epidemic events with lengthening of the inter-outbreak interval. This effect prevails over the seasonal behavior. The scenario of 40% initial reduction in transmissibility is compatible with the behavior of influenza and RSV currently reported in Argentina. DISCUSSION: The general model proposed here, under conditions of temporary reduced transmissibility, shows an epidemiology compatible with recently reported data of influenza and RSV in Argentina. This result illustrates modeling as a useful tool to understand non-intuitive effects.Introducción: Uno de los usos de los modelos matemáticos de la transmisión de enfermedades es el estudio del efecto de diferentes cambios en las condiciones que determinan el comportamiento de las mismas, como la vacunación, las restricciones en la movilidad de las personas o las medidas de cuidado personal. Se sabe que frente a cambios abruptos en los parámetros que representan estas condiciones, los modelos exhiben cambios en la epidemiología, tanto en la magnitud y periodicidad de los brotes como en el perfil etario de la población afectada.  En este trabajo analizamos mediante herramientas de modelado matemático posibles efectos de la pandemia sobre la transmisión de otras enfermedades infecciosas debido a la disminución de la transmisibilidad, como resultado de las medidas de cuidado personal, ventilación y reducción en los contactos sociales adoptados para reducir la circulación de COVID-19. Método: Empleamos un modelo matemático determinista SIRS (susceptible-infectado-recuperado-susceptible) con modulación estacional para representar enfermedades con inmunidad conferida de corta duración y que presentan un ciclo anual. Se utilizaron dos escenarios de parámetros, uno de ellos más apropiado para una enfermedad tipo influenza, con tasa de contagio relativamente baja y con vacuna, y otro más apropiado para una enfermedad tipo virus sincitial respiratorio (VSR), con mayor contagiosidad y sin vacunación. Los cambios en la transmisibilidad de la enfermedad se modelaron reduciéndola durante dos años, planteando distintos escenarios respecto de la reducción de la transmisibilidad. Resultados: La reducción en la transmisibilidad de la enfermedad durante dos años genera cambios en el comportamiento de la enfermedad que se sostienen en los años siguientes: eventos epidémicos pronunciados (que pueden superar los máximos previos) con alargamiento del intervalo interbrote e incluso pérdida del comportamiento estacional típico. Aún en casos en que el inicio de la reducción de la transmisibilidad ocurre en momentos diferentes de un brote (cerca del máximo o cerca del mínimo), su efecto resulta dominante respecto del comportamiento estacional. El escenario de una reducción inicial de la transmisibilidad del 40% resulta compatible con el comportamiento de influenza y VSR reportados actualmente para nuestro país. Discusión: El modelo general propuesto, en determinadas condiciones de baja transitoria en la transmisibilidad, exhibe una epidemiología compatible con la observada recientemente en nuestra región para la influenza y el VSR. Este resultado ilustra el valor del modelado como herramienta útil en la compresión de la transmisión de enfermedades, alertando sobre posibles efectos no intuitivos

Pinning-depinning transition in a stochastic growth model for the evolution of cell colony fronts in a disordered medium

We study a stochastic lattice model for cell colony growth, which takes into account proliferation, diffusion, and rotation of cells, in a culture medium with quenched disorder. The medium is composed both by sites that inhibit any possible change in the internal state of the cells, representing the disorder, as well as by active medium sites, that do not interfere with the cell dynamics. By means of Monte Carlo simulations we find that the velocity of the growing interface, which is taken as the order parameter of the model, strongly depends on the density of active medium sites ($ho_A$). In fact, the model presents a (continuous) second-order pinning-depinning transition at a certain critical value of $ho_A^{crit}$, such as for $ho_A>ho_A^{crit}$ the interface moves freely across the disordered medium, but for $ho_AFil: Moglia, Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentina. Fundación Centro de Medicina Nuclear y Molecular Entre Ríos. Departamento de Física Médica; ArgentinaFil: Albano, Ezequiel Vicente. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; ArgentinaFil: Guisoni, Nara Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentin

Mesoscopic oscillations in a single-gene circuit without delay

It is well known that single-gene circuits with negative feedback loop can lead to oscillatory gene expression when they operate with time delay. In order to generate these oscillations many processes can contribute to properly timing such delay. Here we show that the time delay coming from the transitions between internal states of the cis-regulatory system (CRS) can drive sustained oscillations in an auto-repressive single-gene circuit operating in a small volume like a cell. We found that the cooperative binding of repressor molecules is not mandatory for a oscillatory behavior if there are enough binding sites in the CRS. These oscillations depend on an adequate balance between the CRS kinetic, and the synthesis/degradation rates of repressor molecules. This finding suggest that the multi-site CRS architecture plays a key role for oscillatory behavior of gene expression.Instituto de Física de Líquidos y Sistemas BiológicosCentro Regional de Estudios Genómico

Origins: A protein network-based approach to quantify cell pluripotency from scRNA-seq data

Trajectory inference is a common application of scRNA-seq data. However, it is often necessary to previously determine the origin of the trajectories, the stem or progenitor cells. In this work, we propose a computational tool to quantify pluripotency from single cell transcriptomics data. This approach uses the protein-protein interaction (PPI) network associated with the differentiation process as a scaffold and the gene expression matrix to calculate a score that we call differentiation activity. This score reflects how active the differentiation network is in each cell. We benchmark the performance of our algorithm with two previously published tools, LandSCENT (Chen et al., 2019) and CytoTRACE (Gulati et al., 2020), for four healthy human data sets: breast, colon, hematopoietic and lung. We show that our algorithm is more efficient than LandSCENT and requires less RAM memory than the other programs. We also illustrate a complete workflow from the count matrix to trajectory inference using the breast data set. • ORIGINS is a methodology to quantify pluripotency from scRNA-seq data implemented as a freely available R package. • ORIGINS uses the protein-protein interaction network associated with differentiation and the data set expression matrix to calculate a score (differentiation activity) that quantifies pluripotency for each cell.Fil: Senra, Daniela. Universidad Nacional de La Plata. Centro Regional de Estudios Genómicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Guisoni, Nara Cristina. Universidad Nacional de La Plata. Centro Regional de Estudios Genómicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Diambra, Luis Anibal. Universidad Nacional de La Plata. Centro Regional de Estudios Genómicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentin

Interfacial properties in a discrete model for tumor growth

We propose and study, by means of Monte Carlo numerical simulations, a minimal discrete model for avascular tumor growth, which can also be applied for the description of cell cultures in vitro. The interface of the tumor is self-affine and its width can be characterized by the following exponents: (i) the growth exponent β = 0.32 ( 2 ) that governs the early time regime, (ii) the roughness exponent α = 0.49 ( 2 ) related to the fluctuations in the stationary regime, and (iii) the dynamic exponent z = α / β ≃ 1.49 ( 2 ) , which measures the propagation of correlations in the direction parallel to the interface, e.g., ξ ∝ t 1 / z , where ξ is the parallel correlation length. Therefore, the interface belongs to the Kardar-Parisi-Zhang universality class, in agreement with recent experiments of cell cultures in vitro. Furthermore, density profiles of the growing cells are rationalized in terms of traveling waves that are solutions of the Fisher-Kolmogorov equation. In this way, we achieved excellent agreement between the simulation results of the discrete model and the continuous description of the growth front of the culture or tumor.Fil: Moglia, Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; ArgentinaFil: Guisoni, Nara Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; ArgentinaFil: Albano, Ezequiel Vicente. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; Argentin

Pinning-depinning transition in a stochastic growth model for the evolution of cell colony fronts in a disordered medium

We study a stochastic lattice model for cell colony growth, which takes into account proliferation, diffusion, and rotation of cells, in a culture medium with quenched disorder. The medium is composed both by sites that inhibit any possible change in the internal state of the cells, representing the disorder, as well as by active medium sites, that do not interfere with the cell dynamics. By means of Monte Carlo simulations we find that the velocity of the growing interface, which is taken as the order parameter of the model, strongly depends on the density of active medium sites (ρA). In fact, the model presents a (continuous) second-order pinning-depinning transition at a certain critical value of ρ crit A , such as for ρA > ρcritcrit A the interface becomes irreversible pinned by the disorder. By determining the relevant critical exponents, our study reveals that within the depinned phase the interface can be rationalized in terms of the Kardar-Parisi-Zhang universality class, but when approaching the critical threshold, the non-linear term of the Kardar-Parisi-Zhang equation tends to vanish and then the pinned interface belongs to the quenched Edwards-Wilkinson universality class.Instituto de Física de Líquidos y Sistemas Biológico

Interfacial properties in a discrete model for tumor growth

We propose and study, by means of Monte Carlo numerical simulations, a minimal discrete model for avascular tumor growth, which can also be applied for the description of cell cultures in vitro. The interface of the tumor is self-affine and its width can be characterized by the following exponents: (i) the growth exponent β = 0.32 ( 2 ) that governs the early time regime, (ii) the roughness exponent α = 0.49 ( 2 ) related to the fluctuations in the stationary regime, and (iii) the dynamic exponent z = α / β ≃ 1.49 ( 2 ) , which measures the propagation of correlations in the direction parallel to the interface, e.g., ξ ∝ t 1 / z , where ξ is the parallel correlation length. Therefore, the interface belongs to the Kardar-Parisi-Zhang universality class, in agreement with recent experiments of cell cultures in vitro. Furthermore, density profiles of the growing cells are rationalized in terms of traveling waves that are solutions of the Fisher-Kolmogorov equation. In this way, we achieved excellent agreement between the simulation results of the discrete model and the continuous description of the growth front of the culture or tumor.Instituto de Física de Líquidos y Sistemas BiológicosConsejo Nacional de Investigaciones Científicas y Técnica

Promoters Architecture-Based Mechanism for Noise-Induced Oscillations in a Single-Gene Circuit

It is well known that single-gene circuits with negative feedback loop can lead to oscillatory gene expression when they operate with time delay. In order to generate these oscillations many processes can contribute to properly timing such delay. Here we show that the time delay coming from the transitions between internal states of the cis-regulatory system (CRS) can drive sustained oscillations in an auto-repressive single-gene circuit operating in a small volume like a cell. We found that the cooperative binding of repressor molecules is not mandatory for a oscillatory behavior if there are enough binding sites in the CRS. These oscillations depend on an adequate balance between the CRS kinetic, and the synthesis/degradation rates of repressor molecules. This finding suggest that the multi-site CRS architecture can play a key role for oscillatory behavior of gene expression. Finally, our results can also help to synthetic biologists on the design of the promoters architecture for new genetic oscillatory circuits.Fil: Guisoni, Nara Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física de Líquidos y Sistemas Biológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física de Líquidos y Sistemas Biológicos; ArgentinaFil: Monteoliva, D.. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Física; ArgentinaFil: Diambra, Luis Anibal. Universidad Nacional de La Plata. Centro Regional de Estudios Genómicos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Modeling active cell movement with the Potts model

In the last decade, the cellular Potts model has been extensively used to model interacting cell systems at the tissue-level. However, in early applications of this model, cell movement was taken as a consequence of membrane fluctuations due to cell-cell interactions, or as a response to an external chemotactic gradient. Recent findings have shown that eukaryotic cells can exhibit persistent displacements across scales larger than cell size, even in the absence of external signals. Persistent cell motion has been incorporated to the cellular Potts model by many authors in the context of collective motion, chemotaxis and morphogenesis. In this paper, we use the cellular Potts model in combination with a random field applied over each cell. This field promotes a uniform cell motion in a given direction during a certain time interval, after which the movement direction changes. The dynamics of the direction is coupled to a first order autoregressive process. We investigated statistical properties, such as the mean-squared displacement and spatio-temporal correlations, associated to these self-propelled in silico cells in different conditions. The proposed model emulates many properties observed in different experimental setups. By studying low and high density cultures, we find that cell-cell interactions decrease the effective persistent time.Instituto de Investigaciones Fisicoquímicas Teóricas y AplicadasCentro Regional de Estudios Genómico