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At least 397 records · Page 22Linked to original sources

arXiv2018

Designing diagnostic platforms for analysis of disease patterns and probing disease emergence

The emerging era of personalized medicine relies on medical decisions, practices, and products being tailored to the individual patient. Point-of-care systems, at the heart of this model, play two important roles. First, they are required for identifying subjects for optimal therapies based on their genetic make-up and epigenetic profile. Second, they will be used for assessing the progression of such therapies. Central to this vision is designing systems that, with minimal user-intervention, can transduce complex signals from biosystems in complement with clinical information to inform medical decision within point-of-care settings. To reach our ultimate goal of developing point-of-care systems and realizing personalized medicine, we are taking a multistep systems-level approach towards understanding cellular processes and biomolecular profiles, to quantify disease states and external interventions.

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arXiv2018

Coagulation model for ion channels in the lipid membranes

A two-dimensional (2D) model is developed to describe the growth of spotty patterns (domains) in the lipid membranes which result from the coagulation of ion channels. It is assumed that the ion channels can coagulate when activated, e.g. the neurotransmitter may act as the surface-active substance for some ion channels in the lipid matrix or the activation may result in increase of polarity of the ion channels that give rise to their coagulation process due to the Brownian diffusive motion. The results show that the domain radius rD of the ion channels scales with time as rD~time^0.4.The slowing and subsequent saturation of the domain radius at longer time periods are in qualitative agreement with experiments.

physics.bio-ph↗

arXiv2018

Nanopore occlusion: A biophysical mechanism for bipolar cancellation in cell membranes

Extraordinarily large but short electric field pulses are reported by many experiments to cause bipolar cancellation (BPC). This unusual cell response occurs if a first pulse is followed by a second pulse with opposite polarity. Possibly universal, BPC presently lacks a mechanistic explanation. Multiple versions of the "standard model" of cell electroporation (EP) fail to account for BPC. Here we show, for the first time, how an extension of the standard model can account for a key experimental observation that essentially defines BPC: the amount of a tracer that enters a cell, and how tracer influx can be decreased by the second part of a bipolar pulse. The extended model can also account for the recovery of BPC wherein the extent of BPC is diminished if the spacing between the first and second pulses is increased. Our approach is reverse engineering, meaning that we identify and introduce an additional biophysical mechanism that allows pore transport to change. We hypothesize that occluding molecules from outside the membrane enter or relocate within a pore. Significantly, the additional mechanism is fundamental and general, involving a combination of partitioning and hindrance. Molecules near the membrane can enter pores to block transport of tracer molecules while still passing small ions (+/- 1) that govern electrical behavior. Accounting for such behavior requires an extension of the standard model.

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arXiv2018

Non-associative learning in intra-cellular signaling networks

Nonlinear systems driven by recurrent signals are known to exhibit complex dynamical responses which, in the physiological context, can have important functional consequences. One of the simplest biological systems that is exposed to such repeated stimuli is the intra-cellular signaling network. In this paper we investigate the periodic activation of an evolutionarily conserved motif of this network, viz., the mitogen-activated protein kinase (MAPK) signaling cascade, with a train of pulses. The resulting response of the cascade, which shows integrative capability over several successive pulses, is characterized by complex adaptive behavior. These include aspects of non-associative learning, in particular, habituation and sensitization, which are observed in response to high- and low-frequency stimulation, respectively. In addition, the existence of a response threshold of the cascade, an apparent refractory behavior following stimulation with short inter-pulse interval, and an alternans-like response under certain conditions suggest an analogy with excitable media.

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arXiv2018

Ribosome self-assembly leads to overlapping reproduction cycles and increases growth rate

In permissive environments, E. coli can double its dry mass every 21 minutes. During this time, ribosomes, RNA polymerases, and the proteome are all doubled. Yet, the question of how to relate bacterial doubling time to other biologically relevant time scales in the growth process remains illusive, due to the complex temporal nesting pattern of these processes. In particular, the relation between the cell's doubling time and the ribosome assembly time is not known. Here we develop a model that connects growth rate to ribosome assembly time and show that the existence of a self-assembly step increases the overall growth rate, because during ribosome self-assembly existing ribosomes can start a new round of reproduction, by making a new batch of ribosomal proteins prior to the completion of the previous round. This overlapping of ribosome reproduction cycles increases growth rate beyond the serial-limit that is typically assumed to hold. Using recent data from ribosome profiling and well known measurements of the average translation rate, rigid bounds on the in-vivo ribosome self-assembly time are set, which are robust to the assumptions regarding the biological noises involved. At 21 minutes doubling time, the ribosome assembly time is found to be approximately 6 minutes --- three fold larger than the common estimate. We further use our model to explain the detrimental effect of a recently discovered ribosome assembly inhibitor drug, and predict the effect of limiting the expression of ribosome assembly chaperons on the overall growth rate.

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arXiv2018

Boundary lipids of the nicotinic acetylcholine receptor: spontaneous partitioning via coarse-grained molecular dynamics simulation

Reconstituted nicotinic acetylcholine receptors (nAChRs) exhibit significant gain-of-function upon addition of cholesterol to reconstitution mixtures, and cholesterol affects organization of nAChRs within domain-forming membranes, but whether nAChR partitions to cholesterol-rich liquid-ordered ("raft" or $l_o$) domains or cholesterol-poor liquid-disordered ($l_{do}$) domains is unknown. We use coarse-grained molecular dynamics simulations to observe spontaneous interactions of cholesterol, saturated lipids, and polyunsaturated (PUFA) lipids with nAChRs. In binary Dipalmitoylphosphatidylcholine:Cholesterol (DPPC:CHOL) mixtures, both CHOL and DPPC acyl chains were observed spontaneously entering deep "non-annular" cavities in the nAChR TMD, particularly at the subunit interface and the $β$ subunit center, facilitated by the low amino acid density in the cryo-EM structure of nAChR in a native membrane. Cholesterol was highly enriched in the annulus around the TMD, but this effect extended over (at most) 5-10Å. In domain-forming ternary mixtures containing PUFAs, the presence of a single receptor did not significantly affect the likelihood of domain formation. nAChR partitioned to any cholesterol-poor $l_{do}$ domain that was present, regardless of whether the $l_{do}$ or $l_o$ domain lipids had PC or PE headgroups. Enrichment of PUFAs among boundary lipids was positively correlated with their propensity for demixing from cholesterol-rich phases. Long $n - 3$ chains (tested here with Docosahexaenoic Acid, DHA) were highly enriched in annular and non-annular embedded sites, partially displacing cholesterol and completely displacing DPPC, and occupying sites even deeper within the bundle. Shorter $n - 6$ chains were far less effective at displacing cholesterol from non-annular sites.

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arXiv2018

Mechanisms of Protein Search for Targets on DNA: Theoretical Insights

Protein-DNA interactions are critical for the successful functioning of all natural systems. The key role in these interactions is played by processes of protein search for specific sites on DNA. Although it has been studied for many years, only recently microscopic aspects of these processes became more clear. In this work, we present a review on current theoretical understanding of the molecular mechanisms of the protein target search. A comprehensive discrete-state stochastic method to explain the dynamics of the protein search phenomena is introduced and explained. Our theoretical approach utilizes a first-passage analysis and it takes into account the most relevant physical-chemical processes. It is able to describe many fascinating features of the protein search, including unusually high effective association rates, high selectivity and specificity, and the robustness in the presence of crowders and sequence heterogeneity.

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arXiv2018

Quantification of flux for non-equilibrium dynamics and thermodynamics for driving non-Michaelis-Menton Enzyme Rates

The driving force for active physical and biological systems is determined by both the underlying landscape and the non-equilibrium curl flux. While landscape can be quantified in the experiments by the histograms of the collecting trajectories of the observables, the experimental flux quantification is still challenging. In this work, we studied the single molecule enzyme dynamics and observed the deviation in kinetics from the conventional Michaelis-Menton reaction rate. We identified and quantified the non-equilibrium flux as the origin of such non-Michaelis-Menton enzyme rate behavior. This is the first time of rigorous quantification of the flux for the driving force of the non-equilibrium active dynamics. We also quantified the corresponding non-equilibrium thermodynamics in terms of chemical potential and entropy production. We identified and quantified the origin of the flux, chemical potential and entropy production as the heat absorbed (energy input) in the enzyme reaction.

physics.bio-ph↗

arXiv2018

Transport Facilitated by Rapid Binding to Elastic Tethers

Diffusion in cell biology is important and complicated. Diffusing particles must contend with a complex environment as they make their way through the cell. We analyze a particular type of complexity that arises when diffusing particles reversibly bind to elastically tethered binding partners. Using asymptotic analysis, we derive effective equations for the transport of both single and multiple particles in the presence of such elastic tethers. We show that for the case of linear elasticity and simple binding kinetics, the elastic tethers have a weak hindering effect on particle motion when only one particle is present, while, remarkably, strongly enhancing particle motion when multiple particles are present. We give a physical interpretation of this result that suggests a similar effect may be present in other biological settings.

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arXiv2018

Spatial control of irreversible protein aggregation

Liquid cellular compartments spatially segregate from the cytoplasm and can regulate aberrant protein aggregation, a process linked to several medical conditions, including Alzheimer's and Parkinson's diseases. Yet the mechanisms by which these droplet-like compartments affect protein aggregation remain unknown. Here, we combine kinetic theory of protein aggregation and liquid-liquid phase separation to study the spatial control of irreversible protein aggregation in the presence of liquid compartments. We find that, even for weak interactions between the compartment constituents and the aggregating monomers, aggregates are strongly enriched inside the liquid compartment relative to the surrounding cytoplasm. We show that this enrichment is caused by a positive feedback mechanism of aggregate nucleation and growth which is mediated by a flux maintaining the phase equilibrium between the compartment and the cytoplasm. Our model predicts that the compartment volume that maximizes aggregate enrichment in the compartment is determined by the reaction orders of aggregate nucleation. The underlying mechanism of aggregate enrichment could be used to confine cytotoxic protein aggregates inside droplet-like compartments suggesting potential new avenues against aberrant protein aggregation. Our findings could also represent a common mechanism for the spatial control of irreversible chemical reactions in general.

physics.bio-ph↗

arXiv2018

Stochastic Simulation to Visualize Gene Expression and Error Correction in Living Cells

Stochastic simulation can make the molecular processes of cellular control more vivid than the traditional differential-equation approach by generating typical system histories instead of just statistical measures such as the mean and variance of a population. Simple simulations are now easy for students to construct from scratch, that is, without recourse to black-box packages. In some cases, their results can also be compared directly to single-molecule experimental data. After introducing the stochastic simulation algorithm, this article gives two case studies, involving gene expression and error correction, respectively. Code samples and resulting animations showing results are given in the online supplements.

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arXiv2018

Autoamplification and competition drive symmetry breaking: Initiation of centriole duplication by the PLK4-STIL network

Symmetry breaking, a central principle of physics, has been hailed as the driver of self-organization in biological systems in general and biogenesis of cellular organelles in particular, but the molecular mechanisms of symmetry breaking only begin to become understood. Centrioles, the structural cores of centrosomes and cilia, must duplicate every cell cycle to ensure their faithful inheritance through cellular divisions. Work in model organisms identified conserved proteins required for centriole duplication and found that altering their abundance affects centriole number. However, the biophysical principles that ensure that, under physiological conditions, only a single procentriole is produced on each mother centriole remain enigmatic. Here we propose a mechanistic biophysical model for the initiation of procentriole formation in mammalian cells. The model faithfully recapitulates the experimentally observed transition from PLK4 uniformly distributed around the mother centriole, the "ring", to a unique PLK4 focus, the "spot", that triggers the assembly of a new procentriole. This symmetry breaking requires a dual positive feedback based on autocatalytic activation of PLK4 and enhanced centriolar anchoring of PLK4-STIL complexes by phosphorylated STIL. We find that, contrary to previous proposals, in situ degradation of active PLK4 is insufficient to break symmetry. Instead, the model predicts that competition between transient PLK4 activity maxima for PLK4-STIL complexes explains both the instability of the PLK4 ring and formation of the unique PLK4 spot. In the model, strong competition at physiologically normal parameters robustly produces a single procentriole, while increasing overexpression of PLK4 and STIL weakens the competition and causes progressive addition of procentrioles in agreement with experimental observations.

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arXiv2018

Effect Of Site Selective Ion Channel Blocking on Action Potential

In this work we have theoretically investigated how the action potential generation and its associated intrinsic properties are affected in presence of ion channel blockers by adapting Gillepie's stochastic simulation technique on a very basic neuron of Hodgkin-Huxley type. With a simple extension of the Hodgkin-Huxley Markov model we have mainly investigated three types of drug blocking mechanisms and showed that the major experimental and physiological observations such as ionic currents, spiking frequency trends, change in action potential shape and duration, altered gating dynamics etc due to the presence of ion channel blockers can be well reproduced. The nature of action potential termination process in presence of sodium and potassium channel blockers are distinct and physiologically very different from each other. Channel blockers have distinct signatures on ionic currents. In presence of only sodium channel blockers the frequency of action potential generation falls off exponentially with increasing drug affinity, whereas in contrast, for only potassium channel blockers initially an enhanced spiking activity of action potential is found followed by a gradual decrease of the spiking frequency as the drug affinity increases. In case of dual type blockers with equal sodium and potassium channel binding affinity, the spiking frequency passes through maxima and minima due to the competition between channel number fluctuation and overall sodium and potassium conductances. We have found that sodium channel blockers shorten the duration of action potential while the potassium channel blockers delay it. We have also shown how the ion channel blockers alter the gating dynamics. Some experimental results of ion channel blocking in diverse systems have been validated through our site selected binding scheme.

physics.bio-ph↗

arXiv2018

Kinetics of Vesicle Growth

A mechanism is proposed for the growth of vesicles dispersed in a liquid solvent and a size distribution function is obtained for the vesicles, both from the first principles calculations. This distribution function is shown to be positively skewed and evolving in time obeying a Fokker-Planck type equation. The critical size of the spherical vesicles is shown to grow in time with an exponent of 0.25. A constant is suggested that characterizes how easily a vesicle can absorb amphiphiles into its periphery.

physics.bio-ph↗

arXiv2018

First-passage processes on a filamentous track in a dense traffic: optimizing diffusive search for a target in crowding conditions

Several important biological processes are initiated by the binding of a protein to a specific site on the DNA. The strategy adopted by a protein, called transcription factor (TF), for searching its specific binding site on the DNA has been investigated over several decades. In recent times the effects obstacles, like DNA-binding proteins, on the search by TF has begun to receive attention. RNA polymerase (RNAP) motors collectively move along a segment of the DNA during a genomic process called transcription. This RNAP traffic is bound to affect the diffusive scanning of the same segment of the DNA by a TF searching for its binding site. Motivated by this phenomenon, here we develop a kinetic model where a `particle', that represents a TF, searches for a specific site on a one-dimensional lattice. On the same lattice another species of particles, each representing a RNAP, hop from left to right exactly as in a totally asymmetric simple exclusion process (TASEP) which forbids simultaneous occupation of any site by more than one particle, irrespective of their identities. Although the TF is allowed to attach to or detach from any lattice site, the RNAPs can attach only to the first site at the left edge and detach from only the last site on the right edge of the lattice. We formulate the search as a {\it first-passage} process; the time taken to reach the target site {\it for the first time}, starting from a well defined initial state, is the search time. By approximate analytical calculations and Monte Carlo (MC) computer simulations, we calculate the mean search time. We show that RNAP traffic rectifies the diffusive motion of TF to that of a Brownian ratchet, and the mean time of successful search can be even shorter than that required in the absence of RNAP traffic. Moreover, we show that there is an optimal rate of detachment that corresponds to the shortest mean search time.

physics.bio-ph↗

arXiv2018

Active unidirectional network flow generates a packet molecular transport in cells

Internet, social media, neuronal or blood vessel are organized in complex networks. These networks are characterized by several quantities such as the underlying graph connectivity (topology), how they grow in time, scaling laws or by the mean time a random search can cover a network and also by shortest path between two nodes. We present here a novel type of network property based on a unidirectional transport mechanism occurring in the Endoplasmic Reticulum network found in the cell cytoplasm. This mechanism is an active-waiting transportation, where molecules have to wait a random time before being transported from one node to the next one. We find that the consequence of this unusual network transportation is that molecules travel together by recurrent packets, which quite a large deviation behavior compared to classical propagation in graphs. To conclude, this form of transportation is associated with an efficient and robust molecular redistribution inside cells.

q-bio.SC↗

arXiv2018

Mechanical factors affecting the mobility of membrane proteins

The mobility of membrane proteins controls many biological functions. The application of the model of Saffman and Delbrück to the diffusion of membrane proteins does not account for all the experimental measurements. These discrepancies have triggered a lot of studies on the role of the mechanical factors in the mobility. After a short review of the Saffman and Delbrück model and of some key experiments, we explore the various ways to incorporate the effects of the different mechanical factors. Our approach focuses on the coupling of the protein to the membrane, which is the central element in the modelling. We present a general, polaron-like model, its recent application to the mobility of a curvature sensitive protein, and its various extensions to other couplings that may be relevant in future experiments.

physics.bio-ph↗

arXiv2019

Most Probable Evolution Trajectories in a Genetic Regulatory System Excited by Stable Lévy Noise

We study the most probable trajectories of the concentration evolution for the transcription factor activator in a genetic regulation system, with non-Gaussian stable Lévy noise in the synthesis reaction rate taking into account. We calculate the most probable trajectory by spatially maximizing the probability density of the system path, i.e., the solution of the associated nonlocal Fokker-Planck equation. We especially examine those most probable trajectories from low concentration state to high concentration state (i.e., the likely transcription regime) for certain parameters, in order to gain insights into the transcription processes and the tipping time for the transcription likely to occur. This enables us: (i) to visualize the progress of concentration evolution (i.e., observe whether the system enters the transcription regime within a given time period); (ii) to predict or avoid certain transcriptions via selecting specific noise parameters in particular regions in the parameter space. Moreover, we have found some peculiar or counter-intuitive phenomena in this gene model system, including (a) a smaller noise intensity may trigger the transcription process, while a larger noise intensity can not, under the same asymmetric Lévy noise. This phenomenon does not occur in the case of symmetric Lévy noise; (b) the symmetric Lévy motion always induces transition to high concentration, but certain asymmetric Lévy motions do not trigger the switch to transcription. These findings provide insights for further experimental research, in order to achieve or to avoid specific gene transcriptions, with possible relevance for medical advances.

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