Physical biology最新文献

Cell-to-cell variability in protein concentrations is strongly affected by extrinsic noise, especially for highly expressed genes. Extrinsic noise can be due to fluctuations of several possible cellular factors connected to cell physiology and to the level of key enzymes in the expression process. However, how to identify the predominant sources of extrinsic noise in a biological system is still an open question. This work considers a general stochastic model of gene expression with extrinsic noise represented as fluctuations of the different model rates, and focuses on the out-of-equilibrium expression dynamics. Combining analytical calculations with stochastic simulations, we characterize how extrinsic noise shapes the protein variability during gene activation or inactivation, depending on the prevailing source of extrinsic variability, on its intensity and timescale. In particular, we show that qualitatively different noise profiles can be identified depending on which are the fluctuating parameters. This indicates an experimentally accessible way to pinpoint the dominant sources of extrinsic noise using time-coarse experiments.

Eukaryotic chromosomes exhibit a hierarchical organization that spans a spectrum of length scales, ranging from sub-regions known as loops, which typically comprise hundreds of base pairs, to much larger chromosome territories that can encompass a few mega base pairs. Chromosome conformation capture experiments that involve high-throughput sequencing methods combined with microscopy techniques have enabled a new understanding of inter- and intra-chromosomal interactions with unprecedented details. This information also provides mechanistic insights on the relationship between genome architecture and gene expression. In this article, we review the recent findings on three-dimensional interactions among chromosomes at the compartment, topologically associating domain, and loop levels and the impact of these interactions on the transcription process. We also discuss current understanding of various biophysical processes involved in multi-layer structural organization of chromosomes. Then, we discuss the relationships between gene expression and genome structure from perturbative genome-wide association studies. Furthermore, for a better understanding of how chromosome architecture and function are linked, we emphasize the role of epigenetic modifications in the regulation of gene expression. Such an understanding of the relationship between genome architecture and gene expression can provide a new perspective on the range of potential future discoveries and therapeutic research.

In the brain, both neurons and glial cells work in conjunction with each other during information processing. Stimulation of neurons can induce calcium oscillations in astrocytes which in turn can affect neuronal calcium dynamics. The 'glissandi' effect is one such phenomenon, associated with a decrease in infraslow fluctuations, in which synchronized calcium oscillations propagate as a wave in hundreds of astrocytes. Nitric oxide molecules released from the astrocytes contribute to synaptic functions based on the underlying astrocyte-neuron interaction network. In this study, by defining an astrocyte-neuronal (A-N) calcium unit as an integrated circuit of one neuron and one astrocyte, we developed a minimal model of neuronal stimulus-dependent and NO-mediated emergence of calcium waves in astrocytes. Incorporating inter-unit communicationviaNO molecules, a coupled network of 1000 such A-N calcium units is developed in which multiple stable regimes were found to emerge in astrocytes. We examined the ranges of neuronal stimulus strength and the coupling strength between A-N calcium units that give rise to such dynamical behaviors. We also report that there exists a range of coupling strength, wherein units not receiving stimulus also start showing oscillations and become synchronized. Our results support the hypothesis that glissandi-like phenomena exhibiting synchronized calcium oscillations in astrocytes help in efficient synaptic transmission by reducing the energy demand of the process.

Soil-dwelling microorganisms use a variety of chemical and physical signals to navigate their environment. Plant roots produce endogenous electric fields which result in characteristic current profiles. Such electrical signatures are hypothesised to be used by pathogens and symbionts to track and colonise plant roots. The oomycete pathogenPhytophthora palmivoragenerates motile zoospores which swim towards the positive pole when exposed to an external electric fieldin vitro. Here, we provide a quantitative characterization of their electrotactic behaviour in 3D. We found that a weak electric field (0.7-1.0 V cm^-1) is sufficient to induce an accumulation of zoospore at the positive pole, without affecting their encystment rate. We also show that the same external electric field increases the zoospore germination rate and orients the germ tube's growth. We conclude that several early stages of theP. palmivorainfection cycle are affected by external electric fields. Taken together, our results are compatible with the hypothesis that pathogens use plant endogenous electric fields for host targeting.

Interphase chromosomes are known to organize non-randomly in the micron-sized eukaryotic cell nucleus and occupy certain fraction of nuclear volume, often without mixing. Using extensive coarse-grained simulations, we model such chromosome structures as colloidal particles whose surfaces are grafted by cyclic polymers. This model system is known as Rosetta. The cyclic polymers, with varying polymerization degrees, mimic chromatin loops present in interphase chromosomes, while the rigid core models the chromocenter section of the chromosome. Our simulations show that the colloidal chromosome model provides a well-separated particle distribution without specific attraction between the chain monomers. As the polymerization degree of the grafted cyclic chains decreases while maintaining the total chromosomal length (e.g. the more potent activity of condensin-family proteins), the average chromosomal volume becomes smaller, inter-chromosomal contacts decrease, and chromocenters organize in a quasi-crystalline order reminiscent of a glassy state. This order weakens for polymer chains with a characteristic size on the order of the confinement radius. Notably, linear-polymer grafted particles also provide the same chromocenter organization scheme. However, unlike linear chains, cyclic chains result in less contact between the polymer layers of neighboring chromosome particles, demonstrating the effect of DNA breaks in altering genome-wide contacts. Our simulations show that polymer-grafted colloidal systems could help decipher 3D genome architecture along with the fractal globular and loop-extrusion models.

Coarse-grained descriptions of collective motion of flocking systems are often derived for the macroscopic or the thermodynamic limit. However, the size of many real flocks falls within 'mesoscopic' scales (10 to 100 individuals), where stochasticity arising from the finite flock sizes is important. Previous studies on mesoscopic models have typically focused on non-spatial models. Developing mesoscopic scale equations, typically in the form of stochastic differential equations, can be challenging even for the simplest of the collective motion models that explicitly account for space. To address this gap, here, we take a novel data-driven equation learning approach to construct the stochastic mesoscopic descriptions of a simple, spatial, self-propelled particle (SPP) model of collective motion. In the spatial model, a focal individual can interact withkrandomly chosen neighbours within an interaction radius. We considerk = 1 (called stochastic pairwise interactions),k = 2 (stochastic ternary interactions), andkequalling all available neighbours within the interaction radius (equivalent to Vicsek-like local averaging). For the stochastic pairwise interaction model, the data-driven mesoscopic equations reveal that the collective order is driven by a multiplicative noise term (hence termed, noise-induced flocking). In contrast, for higher order interactions (k > 1), including Vicsek-like averaging interactions, models yield collective order driven by a combination of deterministic and stochastic forces. We find that the relation between the parameters of the mesoscopic equations describing the dynamics and the population size are sensitive to the density and to the interaction radius, exhibiting deviations from mean-field theoretical expectations. We provide semi-analytic arguments potentially explaining these observed deviations. In summary, our study emphasises the importance of mesoscopic descriptions of flocking systems and demonstrates the potential of the data-driven equation discovery methods for complex systems studies.

Mitochondria serve a wide range of functions within cells, most notably via their production of ATP. Although their morphology is commonly described as bean-like, mitochondria often form interconnected networks within cells that exhibit dynamic restructuring through a variety of physical changes. Further, though relationships between form and function in biology are well established, the extant toolkit for understanding mitochondrial morphology is limited. Here, we emphasize new and established methods for quantitatively describing mitochondrial networks, ranging from unweighted graph-theoretic representations to multi-scale approaches from applied topology, in particular persistent homology. We also show fundamental relationships between mitochondrial networks, mathematics, and physics, using ideas of graph planarity and statistical mechanics to better understand the full possible morphological space of mitochondrial network structures. Lastly, we provide suggestions for how examination of mitochondrial network form through the language of mathematics can inform biological understanding, and vice versa.

This study describes a method for controlling the production of protein in individual cells using stochastic models of gene expression. By combining modern microscopy platforms with optogenetic gene expression, experimentalists are able to accurately apply light to individual cells, which can induce protein production. Here we use a finite state projection based stochastic model of gene expression, along with Bayesian state estimation to control protein copy numbers within individual cells. We compare this method to previous methods that use population based approaches. We also demonstrate the ability of this control strategy to ameliorate discrepancies between the predictions of a deterministic model and stochastic switching system.

Correlation analysis and its close variant principal component analysis are tools widely applied to predict the biological functions of macromolecules in terms of the relationship between fluctuation dynamics and structural properties. However, since this kind of analysis does not necessarily imply causation links among the elements of the system, its results run the risk of being biologically misinterpreted. By using as a benchmark the structure of ubiquitin, we report a critical comparison of correlation-based analysis with the analysis performed using two other indicators, response function and transfer entropy, that quantify the causal dependence. The use of ubiquitin stems from its simple structure and from recent experimental evidence of an allosteric control of its binding to target substrates. We discuss the ability of correlation, response and transfer-entropy analysis in detecting the role of the residues involved in the allosteric mechanism of ubiquitin as deduced by experiments. To maintain the comparison as much as free from the complexity of the modeling approach and the quality of time series, we describe the fluctuations of ubiquitin native state by the Gaussian network model which, being fully solvable, allows one to derive analytical expressions of the observables of interest. Our comparison suggests that a good strategy consists in combining correlation, response and transfer entropy, such that the preliminary information extracted from correlation analysis is validated by the two other indicators in order to discard those spurious correlations not associated with true causal dependencies.