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arXiv2017

Generative Modeling with Conditional Autoencoders: Building an Integrated Cell

We present a conditional generative model to learn variation in cell and nuclear morphology and the location of subcellular structures from microscopy images. Our model generalizes to a wide range of subcellular localization and allows for a probabilistic interpretation of cell and nuclear morphology and structure localization from fluorescence images. We demonstrate the effectiveness of our approach by producing photo-realistic cell images using our generative model. The conditional nature of the model provides the ability to predict the localization of unobserved structures given cell and nuclear morphology.

stat.ML↗

arXiv2017

Ribosome Flow Model with Extended Objects

We study a deterministic mechanistic model for the flow of ribosomes along the mRNA molecule, called the ribosome flow model with extended objects (RFMEO). This model encapsulates many realistic features of translation including non-homogeneous transition rates along the mRNA, the fact that every ribosome covers several codons, and the fact that ribosomes cannot overtake one another. The RFMEO is a mean-field approximation of an important model from statistical mechanics called the totally asymmetric simple exclusion process with extended objects (TASEPEO). We demonstrate that the RFMEO describes biophysical aspects of translation better than previous mean-field approximations, and that its predictions correlate well with those of TASEPEO. However, unlike TASEPEO, the RFMEO is amenable to rigorous analysis using tools from systems and control theory. We show that the ribosome density profile along the mRNA in the RFMEO converges to a unique steady-state density that depends on the length of the mRNA, the transition rates along it, and the number of codons covered by every ribosome, but not on the initial density of ribosomes along the mRNA. In particular, the protein production rate also converges to a unique steady-state. Furthermore, if the transition rates along the mRNA are periodic with a common period T then the ribosome density along the mRNA and the protein production rate converge to a unique periodic pattern with period T, that is, the model entrains to periodic excitations in the transition rates. We believe that the RFMEO could be useful for modeling, understanding, and re-engineering translation as well as other important biological processes.

q-bio.SC↗

arXiv2017

Optimal Translation Along a Circular mRNA

The ribosome flow model on a ring (RFMR) is a deterministic model for translation of a circularized mRNA. We derive a new spectral representation for the optimal steady-state production rate and the corresponding optimal steady-state ribosomal density in the RFMR. This representation has several important advantages. First, it provides a simple and numerically stable algorithm for determining the optimal values even in very long rings. Second, it enables efficient computation of the sensitivity of the optimal production rate to small changes in the transition rates along the mRNA. Third, it implies that the optimal steady-state production rate is a strictly concave function of the transition rates. Thus maximizing the optimal steady-state production rate with respect to the rates, under an affine constraint on the rates becomes a convex optimization problem that admits a unique solution, which can be determined numerically using highly efficient algorithms. This optimization problem is important, for example, when re-engineering heterologous genes in a host organism. We describe the implications of our results to this and other aspects of translation.

q-bio.SC↗

arXiv2017

Ligand-concentration sensitivity of a multi-state receptor

Biological sensory systems generally operate out of equilibrium, which often leads to their improved performance. Here, we study the sensitivity of ligand concentration for a general receptor model, which is generally in the non-equilibrium stationary state, in the framework of a stochastic diffusion equation. We derived a general formula of the maximum sensitivity. Specifically, the sensitivity is limited universally by the Berg-Purcell limit [Biophys. J ., 1977], regardless of whether the receptor is in an equilibrium or non-equilibrium state.

physics.bio-ph↗

arXiv2017

Spontaneous Oscillations of Elastic Filaments Induced by Molecular Motors

It is known from the wave-like motion of microtubules in motility assays that the piconewton forces that motors produce can be sufficient to bend the filaments. In cellular phenomena such as cytosplasmic streaming, molecular motors translocate along cytoskeletal filaments, carrying cargo which entrains fluid. When large numbers of such forced filaments interact through the surrounding fluid, as in particular stages of oocyte development in $Drosophila~melanogaster$, complex dynamics are observed, but the detailed mechanics underlying them has remained unclear. Motivated by these observations, we study here perhaps the simplest model for these phenomena: an elastic filament, pinned at one end, acted on by a molecular motor treated as a point force. Because the force acts tangential to the filament, no matter what its shape, this "follower-force" problem is intrinsically non-variational, and thereby differs fundamentally from Euler buckling, where the force has a fixed direction, and which, in the low Reynolds number regime, ultimately leads to a stationary, energy-minimizing shape. Through a combination of linear stability theory, analytical study of a solvable simplified "two-link" model, and numerical studies of the full elastohydrodynamic equations of motion we elucidate the Hopf bifurcation that occurs with increasing forcing of a filament, leading to flapping motion analogous to the high Reynolds number oscillations of a garden hose with a free end.

cond-mat.soft↗

arXiv2017

Mechanism of light energy transport in the avian retina

We studied intermediate filaments (IFs) in the retina of the Pied flycatcher (Ficedula hypoleuca) in the foveolar zone. Single IFs span Müller cells (MC) lengthwise; cylindrical bundles of IFs (IFBs) appear inside the cone inner segment (CIS) at the outer limiting membrane (OLM) level. IFBs adjoin the cone cytoplasmatic membrane, following lengthwise regularly spaced, forming a skeleton of the CIS, located above the OLM. IFBs follow along the cone outer segment (COS), with single IFs separating from the IFB, touching and entering in-between the light-sensitive disks of the cone membrane. We propose a mechanism of exciton transfer from the inner retinal surface to the visual pigments in the photoreceptor cells. This includes excitation transfer in donor-acceptor systems, from the IF donors to the rhodopsin acceptors, with theoretic efficiency over 80%. This explains high image contrast in fovea and foveola in daylight, while the classical mechanism that describes Müller cells as optical lightguides operates in night vision, with loss of resolution traded for sensitivity. Our theory receives strong confirmation in morphology and function of the cones and pigment cells. In daylight the lateral surface of the photosensor disks is blocked from the (scattered or oblique) light by the pigment cells. Thus the light energy can only get to the cone via intermediate filaments that absorb photons in the Müller cell endfeet and conduct excitons to the cone. Thus, the disks are consumed at their lateral surfaces, moving to the apex of the cone, with new disks produced below. An alternative hypothesis of direct light passing through the cone with its organelles and hitting the lowest disk contradicts morphological evidence, as thus all of the other disks would have no useful function in daylight vision.

physics.bio-ph↗

arXiv2017

Life efficiency does not always increase with the dissipation rate

There does not exist a general positive correlation between important life-supporting properties and the entropy production rate. The simple reason is that nondissipative and time-symmetric kinetic aspects are also relevant for establishing optimal functioning. In fact those aspects are even crucial in the nonlinear regimes around equilibrium where we find biological processing on mesoscopic scales. We make these claims specific via examples of molecular motors, of circadian cycles and of sensory adaptation, whose performance in some regimes is indeed spoiled by increasing the dissipated power. We use the relation between dissipation and the amount of time-reversal breaking to keep the discussion quantitative also in effective models where the physical entropy production is not clearly identifiable.

cond-mat.stat-mech↗

arXiv2017

Extensile actomyosin?

Living cells move thanks to assemblies of actin filaments and myosin motors that range from very organized striated muscle tissue to disordered intracellular bundles. The mechanisms powering these disordered structures are debated, and all models studied so far predict that they are contractile. We reexamine this prediction through a theoretical treatment of the interplay of three well-characterized internal dynamical processes in actomyosin bundles: actin treadmilling, the attachement-detachment dynamics of myosin and that of crosslinking proteins. We show that these processes enable an extensive control of the bundle's active mechanics, including reversals of the filaments' apparent velocities and the possibility of generating extension instead of contraction. These effects offer a new perspective on well-studied in vivo systems, as well as a robust criterion to experimentally elucidate the underpinnings of actomyosin activity.

physics.bio-ph↗

arXiv2017

Continuous attractor-based clocks are unreliable phase estimators

Statistical estimation theory determines the optimal way of estimating parameters of a fluctuating noisy signal. However, if the estimation is performed on unreliable hardware, a sub-optimal estimation procedure can outperform the previously optimal procedure. Here, we compare classes of circadian clocks by viewing them as phase estimators for the periodic day-night light signal. We find that continuous attractor-based free running clocks, such as those found in the cyanobacterium Synechococcus elongatus and humans, are nearly optimal phase estimators since their flat attractor directions efficiently project out light intensity fluctuations due to weather patterns (`external noise'). However, such flat directions also make these continuous limit cycle attractors highly vulnerable to diffusive 'internal noise'. Given such unreliable biochemical hardware, we find that point attractor-based damped clocks, such as those found in a smaller cyanobacterium with low protein copy number, Prochlorococcus marinus, outperform continuous attractor-based clocks. By interpolating between the two types of clocks found in these organisms, we demonstrate a family of biochemical phase estimation strategies that are best suited to different relative strengths of external and internal noise.

cond-mat.stat-mech↗

arXiv2017

Voltage laws for three-dimensional microdomains with cusp-shaped funnels derived from Poisson-Nernst-Planck equations

We study the electro-diffusion properties of a domain containing a cusp-shaped structure in three dimensions when one ionic specie is dominant. The mathematical problem consists in solving the steady-state Poisson-Nernst-Planck (PNP) equation with an integral constraint for the number of charges. A non-homogeneous Neumann boundary condition is imposed on the boundary. We construct an asymptotic approximation for certain singular limits that agree with numerical simulations. Finally, we analyse the consequences of non-homogeneous surface charge density. We conclude that the geometry of cusp-shaped domains influences the voltage profile, specifically inside the cusp structure. The main results are summarized in the form of new three-dimensional electrostatic laws for non-electroneutral electrolytes. We discuss applications to dendritic spines in neuroscience.

q-bio.NC↗

arXiv2017

Active Disassembly and Reassembly of Actin Networks Induces Distinct Biphasic Mechanics

Actin is a key component of the cytoskeleton, which plays central roles in cell motility, division, growth, and tensile strength. To enable this wide range of transient mechanical processes and properties, networks of actin filaments continuously disassemble and reassemble via active de/re-polymerization. However, the question remains as to how de/re-polymerization kinetics of individual actin filaments translate to time-varying mechanics of dis/re-assembling networks. To address this question, to ultimately elucidate the molecular mechanisms that enable cells to exhibit a myriad of transitory mechanical properties, we couple time-resolved active microrheology with microfluidics to measure the time-varying viscoelastic moduli of entangled and crosslinked actin networks during chemically-triggered network disassembly and reassembly. We also develop a corresponding mathematical model that relates the time-evolution of filament length to the resulting time-dependent storage moduli of evolving networks. During disassembly, we find that the moduli exhibit two distinct exponential decays, with experimental time constants of $\sim$169 and $\sim$47 min, which we show arises from a phase transition from a rigid percolated network to a non-rigid regime occurring after $\sim$90 min. During reassembly, measured moduli exhibit linear increase with time for $\sim$90 min, after which steady-state values are achieved. Our theoretical model shows that reassembly mechanics are dominated by elongation kinetics, and that elongation rates are much slower than has been recently assumed. Our measurements shed much needed light onto how polymerization kinetics map to time-varying mechanics of actively evolving cytoskeleton networks, and provide a powerful platform for studying other active and dynamic systems currently under intense investigation.

physics.bio-ph↗

arXiv2017

A model of cell-wall dynamics during sporulation in Bacillus subtilis

To survive starvation, Bacillus subtilis forms durable spores. After asymmetric cell division, the septum grows around the forespore in a process called engulfment, but the mechanism of force generation is unknown. Here, we derived a novel biophysical model for the dynamics of cell-wall remodeling during engulfment based on a balancing of dissipative, active, and mechanical forces. By plotting phase diagrams, we predict that sporulation is promoted by a line tension from the attachment of the septum to the outer cell wall, as well as by an imbalance in turgor pressures in the mother-cell and forespore compartments. We also predict that significant mother-cell growth hinders engulfment. Hence, relatively simple physical principles may guide this complex biological process.

q-bio.SC↗

arXiv2017

Structure and Electrical Properties of DNA Nanotubes Embedded in Lipid Bilayer Membranes

Engineering the synthetic nanopores through lipid bilayer membrane to access the interior of a cell is a long persisting challenge in biotechnology. Here, we demonstrate the stability and dynamics of a tile-based 6-helix DNA nanotube (DNT) embedded in POPC lipid bilayer using the analysis of 0.2 microsecond long equilibrium MD simulation trajectories. We observe that the head groups of the lipid molecules close to the lumen cooperatively tilt towards the hydrophilic sugar-phosphate backbone of DNA and form a toroidal structure around the patch of DNT protruding in the membrane. Further, we explore the effect of ionic concentrations to the in-solution structure and stability of the lipid-DNT complex. Transmembrane ionic current measurements for the constant electric field MD simulation provide the I-V characteristics of the water filled DNT lumen in lipid membrane. With increasing salt concentrations, the measured values of transmembrane ionic conductance of the porous DNT lumen vary from 4.3 nS to 20.6 nS. Simulations of the DNTs with ssDNA and dsDNA overhangs at the mouth of the pore show gating effect with remarkable difference in the transmembrane ionic conductivities for open and close state nanopores.

cond-mat.soft↗

arXiv2017

Nucleus may be the key site of chloroquine antimalarial action and resistance development

The first proposed hypothesis about the mechanism of chloroquine (CQ) action on malaria parasites is DNA intercalation hypothesis which indicates that the site of CQ action is within the nucleus. Later on the interest of research was shifted from nucleus to lysosome due to the report of CQ accumulation within lysosome. The current opinions about CQ action and resistance are mainly based on the results of more than 30-year studies on lysosome, which can be used to explain some facts but still remains incomplete and controversial. Based on recently published papers and our related data it is possible that the key CQ target protein may exist in the nucleus. Development of CQ resistance is probably mainly due to the alteration in the CQ target protein or certain mechanism which prevents CQ from reaching its target protein in the nucleus. In conclusion, the key site of CQ action may be in the nucleus though it has not been well explored while CQ action in lysosome which has been well studied may be secondarily important in CQ action and resistance.

q-bio.SC↗

arXiv2017

Dissipative particle dynamics simulation of critical pore size in a lipid bilayer membrane

We investigate with computer simulations the critical radius of pores in a lipid bilayer membrane. Ilton et al. (2016) recently showed that nucleated pores in a homopolymer film can increase or decrease in size, depending on whether they are larger or smaller than a critical size which scales linearly with film thickness. Using dissipative particle dynamics, a particle-based simulation method, we investigate the same scenario for a lipid bilayer membrane whose structure is determined by lipid-water interactions. We simulate a perforated membrane in which holes larger than a critical radius grow, while holes smaller than the critical radius close, as in the experiment of Ilton et al. (2016). By altering system parameters such as the number of particles per lipid and the periodicity, we also describe scenarios in which pores of any initial size can seal or even remain stable, showing a fundamental difference in the behavior of lipid membranes from polymer films.

cond-mat.soft↗

arXiv2017

Do cells sense time by number of divisions?

Do biological cells sense time by the number of their divisions, a process that ends at senescence? We consider the question "can the cell's perception of time be expressed through the length of the shortest telomere?" The answer is that the absolute time before senescence cannot be expressed by the telomere's length and that a cell can survive many more divisions than intuitively expected. This apparent paradox is due to shortening and elongation of the telomere, which suggests a random walk model of the telomere's length. The model indicates two phases, first, a determinist drift of the length toward a quasi-equilibrium state, and second, persistence of the length near an attracting state for the majority of divisions prior to senescence. The measure of stability of the latter phase is the expected number of divisions at the attractor ("lifetime") prior to crossing a threshold to senescence. The telomerase regulates stability by creating an effective potential barrier that separates statistically the shortest lifetime from the next shortest. The random walk has to overcome the barrier in order to extend the range of the first regime. The model explains how random telomere dynamics underlies the extension of cell survival time.

q-bio.SC↗

arXiv2017

The Linear-Noise Approximation and moment-closure approximations for stochastic chemical kinetics

This is a short review of two common approximations in stochastic chemical and biochemical kinetics. It will appear as Chapter 6 in the book "Quantitative Biology: Theory, Computational Methods and Examples of Models" edited by Brian Munsky, Lev Tsimring and Bill Hlavacek (to be published in late 2017/2018 by MIT Press). All chapter references in this article refer to chapters in the aforementioned book.

q-bio.SC↗

arXiv2017

A comprehensive stochastic computational model of HIV infection from DNA integration to viral burst

Multiple mechanisms in the HIV lifecycle play a role in its ability to evade therapy and become a chronic, difficult-to-treat infection. Within its major cellular target, the activated T cell, many steps occur between viral entry and viral burst, including reverse transcription of viral RNA, integration of the viral DNA in the host genome, viral transcription, splicing, translation, host and viral regulation, and viral packaging. These steps exploit complex networks of macromolecular interactions that exhibit various forms of stochastic behavior. While each of the steps of HIV infection have been individually studied extensively, the combinatorial contribution of rare events in each of the steps, and how series of these rare events lead to different infection phenotypes, are not well understood. The complexity of these processes render experimental study challenging. Therefore, we have built a comprehensive computational model of this large system, by collating the community's knowledge of the infection process. It is a stochastic model where rates of different events in the system are represented as probabilities of the event occurring in a timestep of the simulation. This model enables an understanding of the noise and variation in the system. The model also facilitates a dissected understanding of each small part of the large complex system, and its impact on the overall system dynamics.

q-bio.CB↗