Physical Biology (Phys Biol)

Publications in this journal

• Article: Early signatures of regime shifts in gene expression dynamics.

  Mainak Pal, Amit Kumar Pal, Sayantari Ghosh, Indrani Bose
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  ABSTRACT: Recently, a large number of studies have been carried out on the early signatures of sudden regime shifts in systems as diverse as ecosystems, financial markets, population biology and complex diseases. The signatures of regime shifts in gene expression dynamics are less systematically investigated. In this paper, we consider sudden regime shifts in the gene expression dynamics described by a fold-bifurcation model involving bistability and hysteresis. We consider two alternative models, models 1 and 2, of competence development in the bacterial population B. subtilis and determine some early signatures of the regime shifts between competence and noncompetence. We use both deterministic and stochastic formalisms for the purpose of our study. The early signatures studied include the critical slowing down as a transition point is approached, rising variance and the lag-1 autocorrelation function, skewness and a ratio of two mean first passage times. Some of the signatures could provide the experimental basis for distinguishing between bistability and excitability as the correct mechanism for the development of competence.
  Physical Biology 05/2013; 10(3):036010.
• Article: The fractal spatial distribution of pancreatic islets in three dimensions: a self-avoiding growth model.

  Junghyo Jo, Andreas Hörnblad, German Kilimnik, Manami Hara, Ulf Ahlgren, Vipul Periwal
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  ABSTRACT: The islets of Langerhans, responsible for controlling blood glucose levels, are dispersed within the pancreas. A universal power law governing the fractal spatial distribution of islets in two-dimensional pancreatic sections has been reported. However, the fractal geometry in the actual three-dimensional pancreas volume, and the developmental process that gives rise to such a self-similar structure, has not been investigated. Here, we examined the three-dimensional spatial distribution of islets in intact mouse pancreata using optical projection tomography and found a power law with a fractal dimension of 2.1. Furthermore, based on two-dimensional pancreatic sections of human autopsies, we found that the distribution of human islets also follows a universal power law with a fractal dimension of 1.5 in adult pancreata, which agrees with the value previously reported in smaller mammalian pancreas sections. Finally, we developed a self-avoiding growth model for the development of the islet distribution and found that the fractal nature of the spatial islet distribution may be associated with the self-avoidance in the branching process of vascularization in the pancreas.
  Physical Biology 04/2013; 10(3):036009.
• Article: Lipid droplet organelle distribution in populations of dividing cells studied by simulation.

  Paul Dalhaimer
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  ABSTRACT: One of the key questions in cell biology is how organelles are passed from parent to daughter cells. To help address this question, I used Brownian dynamics to simulate lipid droplets as model organelles in populations of dividing cells. Lipid droplets are dynamic bodies that can form both de novo and by fission, they can also be depleted. The quantitative interplay among these three events is unknown but would seem crucial for controlling droplet distribution in populations of dividing cells. Surprisingly, of the three main events studied: biogenesis, fission, and depletion, the third played the key role in maintaining droplet organelle number-and to a lesser extent volume-in populations of dividing cells where formation events would have seemed paramount. In the case of lipid droplets, this provides computational evidence that they must be sustained, most likely through contacts with the endoplasmic reticulum. The findings also agree with video microscopy experiments over much shorter timescales where droplet depletion in fission yeast cells was not observed. In general, this work shows that organelle maintenance is invaluable and lack thereof cannot necessarily be compensated for by organelle formation. This study provides a time-accurate, physical-based template for long-term cell division studies.
  Physical Biology 04/2013; 10(3):036007.
• Article: Bayesian inference of the lung alveolar spatial model for the identification of alveolar mechanics associated with acute respiratory distress syndrome.

  Scott Christley, Bryanna Emr, Auyon Ghosh, Josh Satalin, Louis Gatto, Yoram Vodovotz, Gary F Nieman, Gary An
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  ABSTRACT: Acute respiratory distress syndrome (ARDS) is acute lung failure secondary to severe systemic inflammation, resulting in a derangement of alveolar mechanics (i.e. the dynamic change in alveolar size and shape during tidal ventilation), leading to alveolar instability that can cause further damage to the pulmonary parenchyma. Mechanical ventilation is a mainstay in the treatment of ARDS, but may induce mechano-physical stresses on unstable alveoli, which can paradoxically propagate the cellular and molecular processes exacerbating ARDS pathology. This phenomenon is called ventilator induced lung injury (VILI), and plays a significant role in morbidity and mortality associated with ARDS. In order to identify optimal ventilation strategies to limit VILI and treat ARDS, it is necessary to understand the complex interplay between biological and physical mechanisms of VILI, first at the alveolar level, and then in aggregate at the whole-lung level. Since there is no current consensus about the underlying dynamics of alveolar mechanics, as an initial step we investigate the ventilatory dynamics of an alveolar sac (AS) with the lung alveolar spatial model (LASM), a 3D spatial biomechanical representation of the AS and its interaction with airflow pressure and the surface tension effects of pulmonary surfactant. We use the LASM to identify the mechanical ramifications of alveolar dynamics associated with ARDS. Using graphical processing unit parallel algorithms, we perform Bayesian inference on the model parameters using experimental data from rat lung under control and Tween-induced ARDS conditions. Our results provide two plausible models that recapitulate two fundamental hypotheses about volume change at the alveolar level: (1) increase in alveolar size through isotropic volume change, or (2) minimal change in AS radius with primary expansion of the mouth of the AS, with the implication that the majority of change in lung volume during the respiratory cycle occurs in the alveolar ducts. These two model solutions correspond to significantly different mechanical properties of the tissue, and we discuss the implications of these different properties and the requirements for new experimental data to discriminate between the hypotheses.
  Physical Biology 04/2013; 10(3):036008.
• Article: Stress generation by myosin minifilaments in actin bundles.

  Nilushi L Dasanayake, Anders E Carlsson
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  ABSTRACT: Forces and stresses generated by the action of myosin minifilaments are analyzed in idealized computer-generated actin bundles, and compared to results for isotropic actin networks. The bundles are generated as random collections of actin filaments in two dimensions with constrained orientations, crosslinked and attached to two fixed walls. Myosin minifilaments are placed on actin filament pairs and allowed to move and deform the network so that it exerts forces on the walls. The vast majority of simulation runs end with contractile minifilament stress, because minifilaments rotate into energetically stable contractile configurations. This process is aided by the bending and stretching of actin filaments, which accomodate minifilament rotation. Stresses for bundles are greater than those for isotropic networks, and antiparallel filaments generate more tension than parallel filaments. The forces transmitted by the actin network to the walls of the simulation cell often exceed the tension in the minifilament itself.
  Physical Biology 04/2013; 10(3):036006.
• Article: Titration and hysteresis in epigenetic chromatin silencing.

  Adel Dayarian, Anirvan M Sengupta
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  ABSTRACT: Epigenetic mechanisms of silencing via heritable chromatin modifications play a major role in gene regulation and cell fate specification. We consider a model of epigenetic chromatin silencing in budding yeast and study the bifurcation diagram and characterize the bistable and the monostable regimes. The main focus of this paper is to examine how the perturbations altering the activity of histone modifying enzymes affect the epigenetic states. We analyze the implications of having the total number of silencing proteins, given by the sum of proteins bound to the nucleosomes and the ones available in the ambient, to be constant. This constraint couples different regions of chromatin through the shared reservoir of ambient silencing proteins. We show that the response of the system to perturbations depends dramatically on the titration effect caused by the above constraint. In particular, for a certain range of overall abundance of silencing proteins, the hysteresis loop changes qualitatively with certain jump replaced by continuous merger of different states. In addition, we find a nonmonotonic dependence of gene expression on the rate of histone deacetylation activity of Sir2. We discuss how these qualitative predictions of our model could be compared with experimental studies of the yeast system under anti-silencing drugs.
  Physical Biology 04/2013; 10(3):036005.
• Article: Biophysics of filament length regulation by molecular motors.

  Hui-Shun Kuan, M D Betterton
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  ABSTRACT: Regulating physical size is an essential problem that biological organisms must solve from the subcellular to the organismal scales, but it is not well understood what physical principles and mechanisms organisms use to sense and regulate their size. Any biophysical size-regulation scheme operates in a noisy environment and must be robust to other cellular dynamics and fluctuations. This work develops theory of filament length regulation inspired by recent experiments on kinesin-8 motor proteins, which move with directional bias on microtubule filaments and alter microtubule dynamics. Purified kinesin-8 motors can depolymerize chemically-stabilized microtubules. In the length-dependent depolymerization model, the rate of depolymerization tends to increase with filament length, because long filaments accumulate more motors at their tips and therefore shorten more quickly. When balanced with a constant filament growth rate, this mechanism can lead to a fixed polymer length. However, the mechanism by which kinesin-8 motors affect the length of dynamic microtubules in cells is less clear. We study the more biologically realistic problem of microtubule dynamic instability modulated by a motor-dependent increase in the filament catastrophe frequency. This leads to a significant decrease in the mean filament length and a narrowing of the filament length distribution. The results improve our understanding of the biophysics of length regulation in cells.
  Physical Biology 04/2013; 10(3):036004.
• Article: Physiological levels of blood coagulation factors IX and X control coagulation kinetics in an in vitro model of circulating tissue factor.

  Garth W Tormoen, Ayesha Khader, András Gruber, Owen J T McCarty
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  ABSTRACT: Thrombosis significantly contributes to cancer morbidity and mortality. The mechanism behind thrombosis in cancer may be circulating tissue factor (TF), as levels of circulating TF are associated with thrombosis. However, circulating TF antigen level alone has failed to predict thrombosis in patients with cancer. We hypothesize that coagulation factor levels regulate the kinetics of circulating TF-induced thrombosis. Coagulation kinetics were measured as a function of individual coagulation factor levels and TF particle concentration. Clotting times increased when pooled plasma was mixed at or above a ratio of 4:6 with PBS. Clotting times increased when pooled plasma was mixed at or above a ratio of 8:2 with factor VII-depleted plasma, 7:3 with factor IX- or factor X-depleted plasmas, or 2:8 with factor II-, V- or VIII-depleted plasmas. Addition of coagulation factors VII, X, IX, V and II to depleted plasmas shortened clotting and enzyme initiation times, and increased enzyme generation rates in a concentration-dependent manner. Only additions of factors IX and X from low-normal to high-normal levels shortened clotting times and increased enzyme generation rates. Our results demonstrate that coagulation kinetics for TF particles are controlled by factor IX and X levels within the normal physiological range. We hypothesize that individual patient factor IX and X levels may be prognostic for susceptibility to circulating TF-induced thrombosis.
  Physical Biology 04/2013; 10(3):036003.
• Article: Effect of deformability difference between two erythrocytes on their aggregation.

  Meongkeun Ju, Swe Soe Ye, Hong Tong Low, Junfeng Zhang, Pedro Cabrales, Hwa Liang Leo, Sangho Kim
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  ABSTRACT: In this study, we investigated the rheology of a doublet that is an aggregate of two red blood cells (RBCs). According to previous studies, most aggregates in blood flow consist of RBC doublet-pairs and thus the understanding of doublet dynamics has scientific importance in describing its hemodynamics. The RBC aggregation tendency can be significantly affected by the cell's deformability which can vary under both physiological and pathological conditions. Hence, we conducted a two-dimensional simulation of doublet dynamics under a simple shear flow condition with different deformability between RBCs. To study the dissociation process of the doublet, we employed the aggregation model described by the Morse-type potential function, which is based on the depletion theory. In addition, we developed a new method of updating fluid property to consider viscosity difference between RBC cytoplasm and plasma. Our results showed that deformability difference between the two RBCs could significantly reduce their aggregating tendency under a shear condition of 50 s(-1), resulting in disaggregation. Since even under physiological conditions, the cell deformability may be significantly different, consideration of the difference in deformability amongst RBCs in blood flow would be needed for the hemodynamic studies based on a numerical approach.
  Physical Biology 04/2013; 10(3):036001.
• Article: Modes of correlated angular motion in live cells across three distinct time scales.

  Andrew W Harrison, David A Kenwright, Thomas A Waigh, Philip G Woodman, Victoria J Allan
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  ABSTRACT: Particle tracking experiments with high speed digital microscopy yield the positions and trajectories of lipid droplets inside living cells. Angular correlation analysis shows that the lipid droplets have uncorrelated motion at short time scales (τ < 1 ms) followed by anti-persistent motion for lag times in the range of 1 ⩽ τ ⩽ 10 ms. The angular correlation at longer time scales, τ > 10 ms, becomes persistent, indicating directed movement. The motion at all time scales is associated with the lipid droplets being tethered to and driven along the microtubule network. The point at which the angular correlation changes from anti-persistent to persistent motion corresponds to the cross over between sub-diffusive and super diffusive motion, as observed by mean square displacement analysis. Correct analysis of the angular correlations of the detector noise is found to be crucial in modelling the observed phenomena.
  Physical Biology 04/2013; 10(3):036002.
• Article: Individual and meta-immune networks.

  Sharron Bransburg-Zabary, Dror Y Kenett, Gittit Dar, Asaf Madi, Yifat Merbl, Francisco J Quintana, Alfred I Tauber, Irun R Cohen, Eshel Ben-Jacob
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  ABSTRACT: Networks can be found everywhere-in technology, in nature and in our bodies. In this paper we present how antigen networks can be used as a model to study network interaction and architecture. Utilizing antigen microarray data of the reactivity of hundreds of antibodies of sera of ten mothers and their newborns, we reconstruct networks, either isotype specific (IgM or IgG) or person specific-mothers or newborns-and investigate the network properties. Such an approach makes it possible to decipher fundamental information regarding the personal immune network state and its unique characteristics. In the current paper we demonstrate how we are successful in studying the interaction between two dependent networks, the maternal IgG repertoire and the one of the offspring, using the concept of meta-network provides essential information regarding the biological phenomenon of cross placental transfer. Such an approach is useful in the study of coupled networks in variety of scientific fields.
  Physical Biology 03/2013; 10(2):025003.
• Article: A one-shot germinal center model under protein structural stability constraints.

  Sana Raoof, Muyoung Heo, Eugene I Shakhnovich
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  ABSTRACT: The germinal center reaction is the process by which low-affinity B cells evolve into potent, immunoglobulin-secreting plasma and memory B cells. Since the recycling hypothesis was created, experimental studies have both tracked movement of a small population of B cells from the light zone into the dark zone, supporting the recycling model, and parallel to the light zone-dark zone interface, indicating a one-way trajectory. We present a novel, sequence-based ab initio model of protein stability and protein interactions. Our model contains a dark zone region of clonal expansion and somatic hypermutation and a light zone site of antigenic selection. We show not only that a one-shot model is sufficient to achieve biologically-realistic rates of affinity growth, population dynamics, and silent:non-silent mutation ratios in the complementary determining region and framework region of antibodies, but also that a stochastic recycling program with or without realistic constraints on the structural stabilities of GC antibodies cannot produce biologically-observed affinity growth, population dynamics or silent:non-silent mutation profiles. The effect of recycling erases affinity gains made by potent antibodies cycling back from the light zone and causes B cells to pool in the dark zone under high replication rates.
  Physical Biology 03/2013; 10(2):025001.
• Article: Diversity of T-cell responses.

  Sean P Stromberg, Jean M Carlson
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  ABSTRACT: Using a dynamic model we study the adaptive immune response to a sequence of two infections. We incorporate lymphocyte diversity by modeling populations as continuous distributions in a multi-dimensional space. As expected, memory cells generated by the primary infection invoke a rapid response when the secondary infection is identical (homologous). When the secondary infection is different (heterologous), the memory cells have a positive effect or no effect at all depending on the similarity of the infections. This model displays 'original antigenic sin' where the average effector affinity for the heterologous infection is lower than it would be for a naive response, but in cases with original antigenic sin we see a reduction in pathogen density. We model pathology resulting from the immune system itself (immunopathology) but find that in cases of original antigenic sin, immunopathology is still reduced. Average effector affinity is not an accurate measure of the quality of an immune response. The effectivity, which is the total pathogen killing rate, provides a direct measure of quality. This quantity takes both affinity and magnitude into account.
  Physical Biology 03/2013; 10(2):025002.
• Article: Physical model of the immune response of bacteria against bacteriophage through the adaptive CRISPR-Cas immune system.

  Pu Han, Liang Ren Niestemski, Jeffrey E Barrick, Michael W Deem
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  ABSTRACT: Bacteria and archaea have evolved an adaptive, heritable immune system that recognizes and protects against viruses or plasmids. This system, known as the CRISPR-Cas system, allows the host to recognize and incorporate short foreign DNA or RNA sequences, called 'spacers' into its CRISPR system. Spacers in the CRISPR system provide a record of the history of bacteria and phage coevolution. We use a physical model to study the dynamics of this coevolution as it evolves stochastically over time. We focus on the impact of mutation and recombination on bacteria and phage evolution and evasion. We discuss the effect of different spacer deletion mechanisms on the coevolutionary dynamics. We make predictions about bacteria and phage population growth, spacer diversity within the CRISPR locus, and spacer protection against the phage population.
  Physical Biology 03/2013; 10(2):025004.
• Article: Multiscale model for the effects of adaptive immunity suppression on the viral therapy of cancer.

  Leticia R Paiva, Hallan S Silva, Silvio C Ferreira, Marcelo L Martins
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  ABSTRACT: Oncolytic virotherapy-the use of viruses that specifically kill tumor cells-is an innovative and highly promising route for treating cancer. However, its therapeutic outcomes are mainly impaired by the host immune response to the viral infection. In this paper, we propose a multiscale mathematical model to study how the immune response interferes with the viral oncolytic activity. The model assumes that cytotoxic T cells can induce apoptosis in infected cancer cells and that free viruses can be inactivated by neutralizing antibodies or cleared at a constant rate by the innate immune response. Our simulations suggest that reprogramming the immune microenvironment in tumors could substantially enhance the oncolytic virotherapy in immune-competent hosts. Viable routes to such reprogramming are either in situ virus-mediated impairing of CD8(+) T cells motility or blockade of B and T lymphocytes recruitment. Our theoretical results can shed light on the design of viral vectors or new protocols with neat potential impacts on the clinical practice.
  Physical Biology 03/2013; 10(2):025005.
• Article: Multi-ion conduction bands in a simple model of calcium ion channels

  I. Kaufman, D.G. Luchinsky, R. Tindjong, P.V.E. McClintock, R.S. Eisenberg
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  ABSTRACT: We report self-consistent Brownian dynamics simulations of a simple electrostatic model of the selectivity filters (SF) of calcium ion channels. They reveal regular structure in the conductance and selectivity as functions of the fixed negative charge Q f at the SF. With increasing Q f , there are distinct regions of high conductance (conduction bands) M0, M1, M2 separated by regions of almost zero-conductance (stop-bands). Two of these conduction bands, M1 and M2, are related to the saturated calcium occupancies of P = 1 and P = 2, respectively and demonstrate self-sustained conductivity. Despite the model's limitations, its M1 and M2 bands show high calcium selectivity and prominent anomalous mole fraction effects and can be identified with the L-type and RyR calcium channels. The non-selective band M0 can be identified with a non-selective cation channel, or with OmpF porin.
  Physical Biology 03/2013; 10(2):026007.
• Article: Transcriptional regulation by histone modifications: towards a theory of chromatin re-organization during stem cell differentiation.

  Hans Binder, Lydia Steiner, Jens Przybilla, Thimo Rohlf, Sonja Prohaska, Jörg Galle
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  ABSTRACT: Chromatin-related mechanisms, as e.g. histone modifications, are known to be involved in regulatory switches within the transcriptome. Only recently, mathematical models of these mechanisms have been established. So far they have not been applied to genome-wide data. We here introduce a mathematical model of transcriptional regulation by histone modifications and apply it to data of trimethylation of histone 3 at lysine 4 (H3K4me3) and 27 (H3K27me3) in mouse pluripotent and lineage-committed cells. The model describes binding of protein complexes to chromatin which are capable of reading and writing histone marks. Molecular interactions of the complexes with DNA and modified histones create a regulatory switch of transcriptional activity. The regulatory states of the switch depend on the activity of histone (de-) methylases, the strength of complex-DNA-binding and the number of nucleosomes capable of cooperatively contributing to complex-binding. Our model explains experimentally measured length distributions of modified chromatin regions. It suggests (i) that high CpG-density facilitates recruitment of the modifying complexes in embryonic stem cells and (ii) that re-organization of extended chromatin regions during lineage specification into neuronal progenitor cells requires targeted de-modification. Our approach represents a basic step towards multi-scale models of transcriptional control during development and lineage specification.
  Physical Biology 03/2013; 10(2):026006.
• Article: Multi-ion conduction bands in a simple model of calcium ion channels.

  I Kaufman, D G Luchinsky, R Tindjong, P V E McClintock, R S Eisenberg
  [show abstract] [hide abstract]
  ABSTRACT: We report self-consistent Brownian dynamics simulations of a simple electrostatic model of the selectivity filters (SF) of calcium ion channels. They reveal regular structure in the conductance and selectivity as functions of the fixed negative charge Qf at the SF. With increasing Qf, there are distinct regions of high conductance (conduction bands) M0, M1, M2 separated by regions of almost zero-conductance (stop-bands). Two of these conduction bands, M1 and M2, are related to the saturated calcium occupancies of P = 1 and P = 2, respectively and demonstrate self-sustained conductivity. Despite the model's limitations, its M1 and M2 bands show high calcium selectivity and prominent anomalous mole fraction effects and can be identified with the L-type and RyR calcium channels. The non-selective band M0 can be identified with a non-selective cation channel, or with OmpF porin.
  Physical Biology 03/2013; 10(2):026007.
• Article: Swimming motility plays a key role in the stochastic dynamics of cell clumping.

  Xianghong Qi, Ricky B Nellas, Matthew W Byrn, Matthew H Russell, Amber N Bible, Gladys Alexandre, Tongye Shen
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  ABSTRACT: Dynamic cell-to-cell interactions are a prerequisite to many biological processes, including development and biofilm formation. Flagellum induced motility has been shown to modulate the initial cell-cell or cell-surface interaction and to contribute to the emergence of macroscopic patterns. While the role of swimming motility in surface colonization has been analyzed in some detail, a quantitative physical analysis of transient interactions between motile cells is lacking. We examined the Brownian dynamics of swimming cells in a crowded environment using a model of motorized adhesive tandem particles. Focusing on the motility and geometry of an exemplary motile bacterium Azospirillum brasilense, which is capable of transient cell-cell association (clumping), we constructed a physical model with proper parameters for the computer simulation of the clumping dynamics. By modulating mechanical interaction ('stickiness') between cells and swimming speed, we investigated how equilibrium and active features affect the clumping dynamics. We found that the modulation of active motion is required for the initial aggregation of cells to occur at a realistic time scale. Slowing down the rotation of flagellar motors (and thus swimming speeds) is correlated to the degree of clumping, which is consistent with the experimental results obtained for A. brasilense.
  Physical Biology 02/2013; 10(2):026005.