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At least 433 records · Page 24Linked to original sources
arXiv2019

Modelling Diffuse Subcellular Protein Structures as Dynamic Social Networks

Fluorescence microscopy has led to impressive quantitative models and new insights gained from richer sets of biomedical imagery. However, there is a dearth of rigorous and established bioimaging strategies for modeling spatiotemporal behavior of diffuse, subcellular components such as mitochondria or actin. In many cases, these structures are assessed by hand or with other semi-quantitative measures. We propose to build descriptive and dynamic models of diffuse subcellular morphologies, using the mitochondrial protein patterns of cervical epithelial (HeLa) cells. We develop a parametric representation of the patterns as a mixture of probability masses. This mixture is iteratively perturbed over time to fit the evolving spatiotemporal behavior of the subcellular structures. We convert the resulting trajectory into a series of graph Laplacians to formally define a dynamic network. Finally, we demonstrate how graph theoretic analyses of the trajectories yield biologically-meaningful quantifications of the structures.

q-bio.SC↗
arXiv2019

Tuning the Transdermal Transport by Application of External Continuous Electric Field: A Molecular Dynamics Coarse-Grained Study

Since a long time the application of small electric potentials on biological membranes (iontophoresis) proved enabling control and improvement of transdermal delivery of substances across this barrier. In spite of a large experimental data, the detailed molecular mechanism of iontophoresis is absent. In the present work the interaction among the external continuous electric field with the outermost layer of the skin (\textit{stratum corneum}) was studied by coarse-grained molecular dynamics. Our results pointed out the occurrence of water-rich vesicles formation depending on the field strength. The corresponding phase diagram indicated that the large set of phenomena (vesicle formation, reversibility, phase transition, disruption) could be completely controlled by tuning external continuous electric fields. Interestingly, electric field shielding effects are in the origin of observed effects and followed a general Arrhenius-like time dependence. Direct current (DC) electric field usage would also have booster diffusion effects due to vesicles creation and reincorporation which would have direct beneficial absorption effects on water-soluble topical agents (vitamins) or dermal jet-injection of drugs by fine needles.

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arXiv2019

Effect of curvature and normal forces on motor regulation of cilia

Cilia are ubiquitous organelles involves in eukaryotic motility. They are long, slender, and motile protrusions from the cell body. They undergo active regular oscillatory beating patterns that can propel cells, such as the algae Chlamydomonas, through fluids. When many cilia beat in synchrony they can also propel fluid along the surfaces of cells, as is the case of nodal cilia. The main structural elements inside the cilium are microtubules. There are also molecular motors of the dynein family that actively power the motion of the cilium. These motors transform chemical energy in the form of ATP into mechanical forces that produce sliding displacement between the microtubules. This sliding is converted to bending by constraints at the base and/or along the length of the cilium. Forces and displacements within the cilium can regulate dyneins and provide a feedback mechanism: the dyneins generate forces, deforming the cilium; the deformations, in turn, regulate the dyneins. This feedback is believed to be the origin of the coordination of dyneins in space and time which underlies the regularity of the beat pattern. Goals and approach. While the mechanism by which dyneins bend the cilium is understood, the feedback mechanism is much less clear. The two key questions are: which forces and displacements are the most relevant in regulating the beat? and how exactly does this regulation occur? In this thesis we develop a framework to describe the spatio-temporal patterns of a cilium with different mechanisms of motor regulation. Characterizing and comparing the predicted shapes and beat patterns of these different mechanisms to those observed in experiments provides us with further understanding on how dyneins are regulated. This comparison is done both, with a linear model that can be analytically solved, as with a non-linear model that we solve numerically.

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arXiv2020

Impact of global structure on diffusive exploration of organelle networks

We investigate diffusive search on planar networks, motivated by tubular organelle networks in cell biology that contain molecules searching for reaction partners and binding sites. Exact calculation of the diffusive mean first-passage time on a spatial network is used to characterize the typical search time as a function of network connectivity. We find that global structural properties --- the total edge length and number of loops --- are sufficient to largely determine network exploration times for a variety of both synthetic planar networks and organelle morphologies extracted from living cells. For synthetic networks on a lattice, we predict the search time dependence on these global structural parameters by connecting with percolation theory, providing a bridge from irregular real-world networks to a simpler physical model. The dependence of search time on global network structural properties suggests that network architecture can be designed for efficient search without controlling the precise arrangement of connections. Specifically, increasing the number of loops substantially decreases search times, pointing to a potential physical mechanism for regulating reaction rates within organelle network structures.

physics.bio-ph↗
arXiv2019

Microtubule Motility Analysis based on Time-Lapse Fluorescence Microscopy

This paper describes an investigation into part of the mechanical mechanisms underlying the formation of mitotic spindle, the cellular machinery responsible for chromosomal separation during cell division. In normal eukaryotic cells, spindles are composed of microtubule filaments that radiate outward from two centrosomes. In many transformed cells, however, centrosome number is misregulated resulting in cells with more than two centrosomes. Addressing the question of how these cells accommodate these additional structures by coalescing supernumerary centrosomes to form normal spindles will provide a powerful insight toward understanding the proliferation of cancer cells and developing new therapeutics. The process of centrosome coalescence is thought to involve motor proteins that function to slide microtubules relative to one another. Here we use in vitro motility assays combined with fluorescence microscopy to visualize, characterize and quantify microtubule-microtubule interactions. After segmenting the microtubules, their speed and direction of movement are the extracted features to cluster their interaction type. In order to evaluate the potential of our processing algorithm, we created a simulated dataset similar to the time-lapse series. Once our procedure has been optimized using the simulated data, we will apply it to the real data. Results of our analyses will provide a quantitative description of interaction among microtubules. This is a potentially important step toward more thorough understanding of cancer.

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arXiv2019

Flexible Cancer-Associated Chromatin Configuration (CACC) Might Be the Fundamental Reason Why Cancer Is So Difficult to Cure

We once proposed that cell-type-associated chromatin configurations determine cell types and that cancer cell type is determined by cancer-associated chromatin configuration (CACC). In this paper, we hypothesize that flexible cell-type-associated chromatin configuration is associated with cell potency and has an advantage over inflexible one in regulating genome related activities, such as DNA replication, DNA transcription, DNA repair, and DNA mutagenesis. The reason why cancer is so difficult to treat is because CACC is flexible, which enables cancer cells not only to produce heterogeneous subclones through limited cell differentiation, but also to maximally and efficiently use genome related resources to survive environmental changes. Therefore, to beat cancer, more efforts should be made to restrict the flexibility of CACC or to change CACC so that cancer cells can be turned back to normal or become less malignant.

q-bio.SC↗
arXiv2019

Frequency and Time Domain Analysis ofsRNA-based Treatment for Inflammatory BowelDisease

The validity of a complex reaction pathway proposed to treat Inflammatory Bowel Disease (IBD) was verified by a comprehensive time and frequency domain analysis. The model was taken to the frequency domain to study the effect and the significance of the negative feedback loop introduced by the reaction pathways. It could be shown that such proposed probiotics have very interesting potentials that could be used extensively in the near future.

q-bio.SC↗
arXiv2019

Towards a theory of assembly of protein complexes: lessons from equilibrium statistical physics

Cellular functions are established through biological evolution, but are constrained by the laws of physics. For instance, the physics of protein folding limits the lengths of cellular polypeptide chains. Consequently, many cellular functions are carried out not by long, isolated proteins, but rather by multi-protein complexes. Protein complexes themselves do not escape physical constraints, one of the most important being the difficulty to assemble reliably in the presence of cellular noise. In order to lay the foundation for a theory of reliable protein complex assembly, we study here an equilibrium thermodynamic model of self-assembly that exhibits four distinct assembly behaviors: diluted protein solution, liquid mixture, "chimeric assembly" and "multifarious assembly". In the latter regime, different protein complexes can coexist without forming erroneous chimeric structures. We show that two conditions have to be fulfilled to attain this regime: (i) the composition of the complexes needs to be sufficiently heterogeneous, and (ii) the use of the set of components by the complexes has to be sparse. Our analysis of publicly available databases of protein complexes indicates that cellular protein systems might have indeed evolved so to satisfy both of these conditions.

physics.bio-ph↗
arXiv2019

Optimizing defence, counter-defence and counter-counter defence in parasitic and trophic interactions -- A modelling study

In host-pathogen interactions, often the host (attacked organism) defends itself by some toxic compound and the parasite, in turn, responds by producing an enzyme that inactivates that compound. In some cases, the host can respond by producing an inhibitor of that enzyme, which can be considered as a counter-counter defence. An example is provided by cephalosporins, beta-lactamases and clavulanic acid (an inhibitor of beta-lactamases). Here, we tackle the question under which conditions it pays, during evolution, to establish a counter-counter defence rather than to intensify or widen the defence mechanisms. We establish a mathematical model describing this phenomenon, based on enzyme kinetics for competitive inhibition. We use an objective function based on Haber's rule, which says that the toxic effect is proportional to the time integral of toxin concentration. The optimal allocation of defence and counter-counter defence can be calculated in an analytical way despite the nonlinearity in the underlying differential equation. The calculation provides a threshold value for the dissociation constant of the inhibitor. Only if the inhibition constant is below that threshold, that is, in the case of strong binding of the inhibitor, it pays to have a counter-counter defence. This theoretical prediction accounts for the observation that not for all defence mechanisms, a counter-counter defence exists. Our results should be of interest for computing optimal mixtures of beta-lactam antibiotics and beta-lactamase inhibitors such as sulbactam, as well as for plant-herbivore and other molecular-ecological interactions and to fight antibiotic resistance in general.

q-bio.SC↗
arXiv2019

Cytoskeletal filament length controlled dynamic sequestering of intracellular cargo

The spatial localization or sequestering of motile cargo and their dispersal within cells is an important process in a number of physiological contexts. The morphology of the cytoskeletal network, along which active, motor-driven intracellular transport takes place, plays a critical role in regulating such transport phases. Here, we use a computational model to address the existence and sensitivity of dynamic sequestering and how it depends on the parameters governing the cytoskeletal network geometry, with a focus on filament lengths and polarization away or toward the periphery. Our model of intracellular transport solves for the time evolution of a probability distribution of cargo that is transported by passive diffusion in the bulk cytoplasm and driven by motors on explicitly rendered, polar cytoskeletal filaments with random orientations. We show that depending on the lengths and polarizations of filaments in the network, dynamic sequestering regions can form in different regions of the cell. Furthermore, we find that, for certain parameters, the residence time of cargo is non-monotonic with increasing filament length, indicating an optimal regime for dynamic sequestration that is potentially tunable via filament length. Our results are consistent with {\it in vivo} observations and suggest that the ability to tunably control cargo sequestration via cytoskeletal network regulation could provide a general mechanism to regulate intracellular transport phases.

physics.bio-ph↗
arXiv2019

Molecular Brightness analysis of GPCR oligomerization in the presence of spatial heterogeneity

Measuring the oligomerization of plasma membrane proteins is rife with biophysical and biomedical implications. This is particularly true for GPCRs, a large family of proteins representing the targets of over one third of all FDA approved medications. Over the last thirty years, fluorescence microscopy has been the leading approach to address this problem. However, in spite of a large number of studies and approaches, for most GPCRs the results have remained highly contentious, possibly due to the large spectrum of specific methods employed.

q-bio.QM↗
arXiv2019

On the Role of Vesicle Transport in Neurite Growth: Modelling and Experiments

The processes that determine the establishment of the complex morphology of neurons during development are still poorly understood. We present experiments that use live imaging to examine the role of vesicle transport and propose a lattice-based model that shows symmetry breaking features similar to a neuron during its polarization. In a otherwise symmetric situation our model predicts that a difference in neurite length increases the growth potential of the longer neurite indicating that vesicle transport can be regarded as a major factor in neurite growth.

q-bio.SC↗
arXiv2019

Stability Analysis of a Bulk-Surface Reaction Model for Membrane-Protein Clustering

Protein aggregation on the plasma membrane (PM) is of critical importance to many cellular processes such as cell adhesion, endocytosis, fibrillar conformation, and vesicle transport. Lateral diffusion of protein aggregates or clusters on the surface of the PM plays an important role in governing their heterogeneous surface distribution. However, the stability behavior of the surface distribution of protein aggregates remains poorly understood. Therefore, understanding the spatial patterns that can emerge on the PM solely through protein-protein interaction, lateral diffusion, and feedback is an important step towards a complete description of the mechanisms behind protein clustering on the cell surface. In this work, we investigate the pattern formation of a reaction-diffusion model that describes the dynamics of a system of ligand-receptor complexes. The purely diffusive ligand in the cytosol can bind receptors in the PM, and the resultant ligand-receptor complexes not only diffuse laterally but can also form clusters resulting in different oligomers. Finally, the largest oligomers recruit ligands from the cytosol in a positive feedback. From a methodological viewpoint, we provide theoretical estimates for diffusion-driven instabilities of the protein aggregates based on the Turing mechanism. Our main result is a threshold phenomenon, in which a sufficiently high recruitment of ligands promotes the input of new monomeric components and consequently drives the formation of a single-patch spatially heterogeneous steady-state.

q-bio.SC↗
arXiv2019

Cell size, mechanical tension, and GTPase signaling in the Single Cell

Cell polarization requires redistribution of specific proteins to the nascent front and back of a eukarytotic cell. Among these proteins are Rac and Rho, members of the small GTPase family that regulate the actin cytoskeleton. Rac promotes actin assembly and protrusion of the front edge, whereas Rho activates myosin-driven contraction at the back. Mathematical models of cell polarization at many levels of detail have appeared. One of the simplest based on "wave-pinning", consists of a pair of reaction-diffusion equations for a single GTPase. Mathematical analysis of wave-pinning so far is largely restricted to static domains in one spatial dimension. Here we extend the analysis to cells that change in size, showing that both shrinking and growing cells can lose polarity. We further consider the feedback between mechanical tension, GTPase activation, and cell deformation in both static, growing, shrinking, and moving cells. Special cases (spatially uniform cell chemistry, absence or presence of mechanical feedback) are analyzed, and the full model is explored by simulations in 1D. We find a variety of novel behaviors, including "dilution-induced" oscillations of Rac activity and cell size, as well as gain or loss of polarization and motility in the model cell.

q-bio.CB↗
arXiv2019

Linear Noise Approximation of Intensity-Driven Signal Transduction Channels

Biochemical signal transduction, a form of molecular communication, can be modeled using graphical Markov channels with input-modulated transition rates. Such channel models are strongly non-Gaussian. In this paper we use a linear noise approximation to construct a novel class of Gaussian additive white noise channels that capture essential features of fully- and partially-observed intensity-driven signal transduction. When channel state transitions that are sensitive to the input signal are directly observable, high-frequency information is transduced more efficiently than low-frequency information, and the mutual information rate per bandwidth (spectral efficiency) is significantly greater than when sensitive transitions and observable transitions are disjoint. When both observable and hidden transitions are input-sensitive, we observe a superadditive increase in spectral efficiency.

q-bio.QM↗
arXiv2019

bcd mRNA active transport: 3D agent-based modeling

The article presents a 3D agent-based model to simulate the dynamics of redistribution of bicoid mRNA. The model is developed on the basis of the Skeledyne software [Odell and Foe, 2008]. The model reproduces active transport by molecular motors over an undirected network of short microtubules. The model is intended to simulate the data presented in [Spirov et al., 2009; Little et al., 2011; Fahmy et al., 2014; Ali-Murthy and Kornberg, 2016; Cai, Spirov, Akber et al., 2017].

q-bio.QM↗
arXiv2019

Brain Energetics, Mitochondria, and Traumatic Brain Injury

We review current thinking about, and draw connections between, brain energetics and metabolism, mitochondria and traumatic brain injury. In addition to summarizing current thinking in these disciplines, our goal is to suggest a framework for mechanisms and pathways based on optimal energetic decisions.

q-bio.CB↗