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At least 163 records · Page 9Linked to original sources

arXiv2011

Toward tunable RNA thermo-switches for temperature dependent gene expression

RNA thermometers are mRNA strands with a temperature dependent secondary structure: depending on the spatial conformation, the mRNA strand can get translated (on-state) or can be inaccessible for ribosomes binding (off-state). These have been found in a number of microorganisms (mainly pathogens), where they are used to adaptively regulate the gene expression, in response to changes in the environmental temperature. Besides naturally occurring RNA thermometers, synthetic RNA thermometers have been recently designed by modifying their natural counterparts (Hofacker et al., 2003). The newly designed RNA thermometers are simpler, and exhibit a sharper switching between off- and on-states. However, the proposed trial-and-error design procedure has not been algorithmically formalized, and the switching temperature is rigidly determined by the natural RNA thermometer used as template for the design. We developed a general algorithmic procedure (consensus distribution) for the design of RNA thermo-switches with a tunable switching temperature that can be decided in advance by the designer. A software tool with a user friendly GUI has been written to automate the design of RNA thermo-switches with a desired threshold temperature. Starting from a natural template, a new RNA thermometer has been designed by our method for a new desired threshold temperature of 32C. The designed RNA thermo-switch has been experimentally validated by using it to control the expression of lucifarase. A 9.2 fold increase of luminescence has been observed between 30C and 37C, whereas between 20C and 30C the luminescence increase is less than 3-fold. This work represents a first step towards the design of flexible and tunable RNA thermometers that can be used for a precise control of gene expression without the need of external chemicals and possibly for temperature measurements at a nano-scale resolution.

q-bio.SC↗

arXiv2011

Thermal Fluctuations of Anisotropic Semiflexible Polymers

Thermal fluctuations of microtubules (MTs) and other cytoskeletal filaments govern to a great extent the complex rheological properties of the cytoskeleton in eukaryotic cells. In recent years, much effort has been put into capturing the dynamics of these fluctuations by means of analytical and numerical models. These attempts have been very successful for, but also remain limited to, isotropic polymers. To correctly interpret experimental work on (strongly) anisotropic semiflexible polymers, there is a need for a numerical modelling tool that accurately captures the dynamics of polymers with anisotropic material properties. In the current study, we present a finite element (FE) framework for simulating the thermal dynamics of a single anisotropic semiflexible polymer. First, we demonstrate the accuracy of our framework by comparison of the simulated mean square displacement (MSD) of the end-to-end distance with analytical predictions based on the worm-like chain model. Then, we implement a transversely isotropic material model, characteristic for biopolymers such as MTs, and study the persistence length for various ratios between the longitudinal shear modulus and corresponding Young's modulus. Finally, we put our findings in context by addressing a recent experimental work on grafted transversely isotropic MTs. In that research, a simplified static mechanical model was used to deduce a very high level of MT anisotropy to explain the observation that the persistence length of grafted MTs increases as contour length increases. We show, by means of our FE framework, that the anisotropic properties cannot account for the reported length-dependent persistence length.

cond-mat.soft↗

arXiv2011

The plasticity of TGF-beta signaling

The family of TGFb ligands is large and its members are involved in many different signaling processes. These signaling processes strongly differ in type with TGFb ligands eliciting both sustained or transient responses. Members of the TGFb family can also act as morphogen and cellular responses would then be expected to provide a direct read-out of the extracellular ligand concentration. We were interested to define the set of minimal modifications that are required to change the type of signal processing in the TGFb signaling network. To define the key aspects for signaling plasticity we focused on the core of the TGFb signaling network. With the help of a parameter screen we identified ranges of kinetic parameters and protein concentrations that give rise to transient, sustained, or oscillatory responses to constant stimuli, as well as those parameter ranges that enable a proportional response to time-varying ligand concentrations (as expected in the read-out of morphogens). A combination of a strong negative feedback and fast shuttling to the nucleus biases signaling to a transient rather than a sustained response, while oscillations were obtained if ligand binding to the receptor is weak and the turn-over of the I-Smad is fast. A proportional read-out required inefficient receptor activation in addition to a low affinity of receptor-ligand binding. We find that targeted modification of single parameters suffices to alter the response type. The architecture of the TGFb pathway enables the observed signaling plasticity. The observed range of signaling outputs to TGFb ligand in different cell types and under different conditions can be explained with differences in cellular protein concentrations and with changes in effective rate constants due to cross-talk with other signaling pathways.

q-bio.MN↗

arXiv2011

Asymptotic Analysis of Microtubule-Based Transport by Multiple Identical Molecular Motors

We describe a system of stochastic differential equations (SDEs) which model the interaction between processive molecular motors, such as kinesin and dynein, and the biomolecular cargo they tow as part of microtubule-based intracellular transport. We show that the classical experimental environment fits within a parameter regime which is qualitatively distinct from conditions one expects to find in living cells. Through an asymptotic analysis of our system of SDEs, we develop a means for applying in vitro observations of the nonlinear response by motors to forces induced on the attached cargo to make analytical predictions for two parameter regimes that have thus far eluded direct experimental observation: 1) highly viscous in vivo transport and 2) dynamics when multiple identical motors are attached to the cargo and microtubule.

math.PR↗

arXiv2011

A new cooperation mechanism of kinesin motors when extracting membrane tube

Membrane tubes are important elements for living cells to organize many functions. Experiments have found that membrane tube can be extracted from giant lipid vesicles by a group of kinesin. How these motors cooperate in extracting the fluid-like membrane tube is still unclear. In this paper, we propose a new cooperation mechanism called two-track-dumbbell model, in which kinesin is regarded as a dumbbell with an end (tail domain) tightly bound onto the fluid-like membrane and the other end (head domain) stepping on or unbinding from the microtubule. Taking account of the elasticity of kinesin molecule and the exclude volume effect of both the head domain and the tail domain of kinesin, which are not considered in previous models, we simulate the growth process of the membrane tube pulled by kinesin motors. Our results indicate that motors along a single microtubule protofilament can generate enough force to extract membrane tubes from vesicles, and the average number of motors pulling the tube is about 8~9. These results are quite different from previous studies (Ref. \cite{camp.08}), and further experimental tests are necessary to elucidate the cooperation mechanism.

physics.bio-ph↗

arXiv2011

Branching actin network remodeling governs the force-velocity relationship

Actin networks, acting as an engine pushing against an external load, are fundamentally important to cell motility. A measure of the effectiveness of an engine is the velocity the engine is able to produce at a given force, the force-velocity curve. One type of force-velocity curve, consisting of a concave region where velocity is insensitive to increasing force followed by a decrease in velocity, is indicative of an adaptive response. In contrast, an engine whose velocity rapidly decays as a convex curve in response to increasing force would indicate a lack of adaptive response. Even taken outside of a cellular context, branching actin networks have been observed to exhibit both concave and convex force-velocity curves. The exact mechanism that can explain both force-velocity curves is not yet known. We carried out an agent-based stochastic simulation to explore such a mechanism. Our results suggest that upon loading, branching actin networks are capable of remodeling by increasing the number filaments growing against the load. Our model provides a mechanism that can account for both convex and concave force-velocity relationships observed in branching actin networks. Finally, our model gives a potential explanation to the experimentally observed force history dependence for actin network velocity.

q-bio.SC↗

arXiv2012

Mechanisms of budding of nanoscale particles through lipid bilayers

We examine the budding of a nanoscale particle through a lipid bilayer using molecular dynamics simulations, free energy calculations, and an elastic theory, with the aim of determining the extent to which equilibrium elasticity theory can describe the factors that control the mechanism and efficiency of budding. The particle is a smooth sphere which experiences attractive interactions to the lipid head groups. Depending on the parameters, we observe four classes of dynamical trajectories: particle adhesion to the membrane, stalled partially wrapped states, budding followed by scission, and membrane rupture. In most regions of parameter space we find that the elastic theory agrees nearly quantitatively with the simulated phase behavior as a function of adhesion strength, membrane bending rigidity, and particle radius. However, at parameter values near the transition between particle adhesion and budding, we observe long-lived partially wrapped states which are not captured by existing elastic theories. These states could constrain the accessible system parameters for those enveloped viruses or drug delivery vehicles which rely on exo- or endocytosis for membrane transport.

q-bio.SC↗

arXiv2012

A solution to the subdiffusion-efficiency paradox: Inactive states enhance reaction efficiency at subdiffusion conditions in living cells

Macromolecular crowding in living biological cells effects subdiffusion of larger biomolecules such as proteins and enzymes. Mimicking this subdiffusion in terms of random walks on a critical percolation cluster, we here present a case study of EcoRV restriction enzymes involved in vital cellular defence. We show that due to its so far elusive propensity to an inactive state the enzyme avoids non-specific binding and remains well-distributed in the bulk cytoplasm of the cell. Despite the reduced volume exploration capability of subdiffusion processes, this mechanism guarantees a high efficiency of the enzyme. By variation of the non-specific binding constant and the bond occupation probability on the percolation network, we demonstrate that reduced non-specific binding are beneficial for efficient subdiffusive enzyme activity even in relatively small bacteria cells. Our results corroborate a more local picture of cellular regulation.

q-bio.SC↗

arXiv2012

Machines of life: catalogue, stochastic process modeling, probabilistic reverse engineering and the PIs- from Aristotle to Alberts

Molecular machines consist of either a single protein or a macromolecular complex composed of protein and RNA molecules. Just like their macroscopic counterparts, each of these nano-machines has an engine that "transduces" input energy into an output form which is then utilized by its coupling to a transmission system for appropriate operations. The theory of heat engines, pioneered by Carnot, rests on the second law of equilibrium thermodynamics. However, the engines of molecular machines, operate under isothermal conditions far from thermodynamic equilibrium. Moreover, one of the possible mechanisms of energy transduction, popularized by Feynman and called Brownian ratchet, does not even have any macroscopic counterpart. But, {\it molecular machine is not synonymous with Brownian ratchet}; a large number of molecular machines actually execute a noisy power stroke, rather than operating as Brownian ratchet. The man-machine analogy, a topic of intense philosophical debate in which many leading philosophers like Aristotle and Descartes participated, was extended to similar analogies at the cellular and subcellular levels after the invention of optical microscope. The idea of molecular machine, pioneered by Marcelo Malpighi, has been pursued vigorously in the last fifty years. It has become a well established topic of current interdisciplinary research as evident from the publication of a very influential paper by Alberts towards the end of the twentieth century. Here we give a non-technical overview of the strategies for (a) stochastic modeling of mechano-chemical kinetic processes, and (b) model selection based on statistical inference drawn from analysis of experimental data. It is written for non-experts and from a broad perspective, showing overlapping concepts from several different branches of physics and from other areas of science and technology.

physics.bio-ph↗

arXiv2012

Living Cell Cytosol Stability to Segregation and Freezing-Out:Thermodynamic aspect

The cytosol state in living cell is treated as homogeneous phase equilibrium with a special feature: the pressure of one phase is positive and the pressure of the other is negative. From this point of view the cytosol is neither solution nor gel (or sol as a whole) regardless its components (water and dissolved substances). This is its unique capability for selecting, sorting and transporting reagents to the proper place of the living cell without a so-called "pipeline". To base this statement the theoretical investigation of the conditions of equilibrium and stability of the medium with alternative-sign pressure is carried out under using the thermodynamic laws and the Gibbs' equilibrium criterium.

physics.gen-ph↗

arXiv2012

Length-dependent dynamics of microtubules

Certain regulatory proteins influence the polymerization dynamics of microtubules by inducing catastrophe with a rate that depends on the microtubule length. Using a discrete formulation, here we show that, for a catastrophe rate proportional to the microtubule length, the steady-state probability distributions of length decay much faster with length than an exponential decay as seen in the absence of these proteins.

physics.bio-ph↗

arXiv2012

Mathematical Modelling of Polarizing GTPases in Developing Axons

The aim of this paper is to contribute to the basic understanding of neuronal polarization mechanisms by developing and studying a reaction-diffusion model for protein activation and inactivation. In particular we focus on a feedback loop between PI3 kinase and certain GTPases, and study its behaviour in dependence of neurite lengths. We find that if an ultrasensitive activation is included, the model can produce polarization at a critical length as observed in experiments. Symmetry breaking to polarization in the longer neurite is found only if active transport of a substance, in our case active PI3 kinase, is included into the model.

q-bio.SC↗

arXiv2012

Reconstructing the free-energy landscape associated to molecular motors processivity

We propose a biochemical model providing the kinetic and energetic descriptions of the processivity dynamics of kinesin and dinein molecular motors. Our approach is a modified version of a well known model describing kinesin dynamics and considers the presence of a competitive inhibition reaction by ADP. We first reconstruct a continuous free-energy landscape of the cycle catalyst process that allows us to calculate the number of steps given by a single molecular motor. Then, we calculate an analytical expression associated to the translational velocity and the stopping time of the molecular motor in terms of time and ATP concentration. An energetic interpretation of motor processivity is discussed in quantitative form by using experimental data. We also predict a time duration of collective processes that agrees with experimental reports.

q-bio.SC↗

arXiv2012

Simple variation of the logistic map as a model to invoke questions on cellular protein trafficking

Many open problems in biology, as in the physical sciences, display nonlinear and 'chaotic' dynamics, which, to the extent possible, cannot be reasonably understood. Moreover, mathematical models which aim to predict/estimate unknown aspects of a biological system cannot provide more information about the set of biologically meaningful (e.g., 'hidden') states of the system than could be understood by the designer of the model ab initio. Here, the case is made for the utilization of such models to shift from a 'predictive' to a 'questioning' nature, and a simple natural-logarithm variation of the logistic polynomial map is presented that can invoke questions about protein trafficking in eukaryotic cells.

q-bio.SC↗

arXiv2012

How to Grow an Organism Inside-Out: Evolution of an internal skeleton from an external skeleton in bilateral organisms

An intriguing unanswered question about the evolution of bilateral animals with internal skeletons is how an internal skeleton evolved in the first place. Computational modeling of the development of bilateral symmetric organisms suggests an answer to this question. Our hypothesis is that an internal skeleton may have evolved from a bilaterally symmetric ancestor with an external skeleton. By growing the organism inside-out an external skeleton becomes an internal skeleton. Our hypothesis is supported by a computational theory of bilateral symmetry that allows us to model and simulate this process. Inside-out development is achieved by an orientation switch. Given the development of two bilateral founder cells that generate a bilateral organism, a mutation that reverses the internal mirror orientation of those bilateral founder cells leads to inside-out development. The new orientation is epigenetically inherited by all progeny. A key insight is that each cell contained in the newly evolved organism with the internal skeleton develops according to the very same downstream developmental control network that directs the development of its exoskeletal ancestor. The networks and their genomes are are identical, but the interpretation is different because of the cell's inverted orientation. The result is inside-out bilateral symmetric development generating an inside-out organism with an internal skeleton.

q-bio.TO↗

arXiv2012

Colorectal cancers differ in respect of PARP-1 protein expression

Recent findings raise the possibility of PARP inhibitor therapy in colorectal cancers(CRCs). However, the extent of PARP-1 protein expression in clinical specimens of CRC is not known. Using immunohistochemistry we assessed PARP-1 protein expression in tissue microarrays of 151 CRCs and its association with the patient's age, sex, Astler-Coller stage, grade and site of the tumor. High PARP nuclear immunoreactivity was found in 68.2% (103/151) of all cases. In turn, 31.8% (48/151)of tumors showed low PARP expression, including 9 (6%) PARP-1 negative CRCs. There was a significant association of PARP-1 expression with the site of CRC and Astler-Coller stage. A high PARP expression was noted in 79.1% of colon vs. 53.9% of rectal tumors (p = 0.001). The mean PARP-1 score was 1.27 times higher in colon vs. rectal cancers (p = 0.009) and it was higher in stage B2 vs. stage C of CRCs (p = 0.018). In conclusion, the level of PARP-1 protein nuclear expression is associated with the tumor site and heterogeneous across clinical specimens of CRC, with the majority of CRCs expressing a high level but minority - low or no PARP-1 expression. These findings may have a clinical significance because the assessment of PARP-1 expression in tumor samples may improve selection of patients with CRC for PARP inhibitor therapy.

q-bio.SC↗

arXiv2012

Routes to Binary Gene Expression

Systems biology approaches combining theoretical modeling with experiments have been singularly successful in uncovering novel features of cellular phenomena. One such feature is that of binary gene expression in which the expression level is either low or high, i.e., digital in nature. This gives rise to two distinct subpopulations in a population of genetically identical cells. The fraction of cells in the high expression state is raised as the strength of the inducing signal is increased indicating that the response is not graded. In this review, we discuss the possible origins of binary gene expression with emphasis on three principal mechanisms: purely stochastic, positive feedback-based and emergent bistability. In the latter case, two stable expression states are obtained due to an autoregulatory positive feedback loop in protein synthesis along with cell growth retardation by the proteins synthesized. The theoretical foundations of the observed phenomena are described in each case.

q-bio.SC↗

arXiv2012

Generalized microscopic theory of ion selectivity in voltage-gated ion channels

Ion channels are specific proteins present in the membranes of living cells. They control the flow of specific ions through a cell, initiated by an ion channel's electrochemical gradient. In doing so, they control important physiological processes such as muscle contraction and neuronal connectivity, which cannot be properly activated if these channels go haywire, leading to life-threatening diseases and psychological disorders. Here, we will develop a generalized microscopic theory of ion selectivity applicable to KcsA, Na$_{\rm v}$Rh and Ca$_{\rm v}$ (L-type) ion channels. We unambiguously expose why and how a given ion-channel can be highly selective, and yet has a conductance of the order of one million ions per second, or higher. We will identify and prove the correct physico-biochemical mechanisms that are responsible for the high selectivity of a particular ion in a given ion channel. The above mechanisms consist of five conditions, which can be directly associated to these parameters - (i) dehydration energy, (ii) concentration of the "correct" ions (iii) Coulomb-van-der-Waals attraction, (iv) pore and ionic sizes, and indirectly to (v) the thermodynamic stability and (vi) the "knock-on" assisted permeation.

q-bio.SC↗