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At least 1,153 records · Page 64Linked to original sources

arXiv2018

The $Ca^{2+}$-activated $Cl^-$ current ensures robust and reliable signal amplification in vertebrate olfactory receptor neurons

Activation of most primary sensory neurons results in transduction currents that are carried by cations. One notable exception is the vertebrate olfactory receptor neuron (ORN), where the transduction current is carried largely by the anion $Cl^-$. However, it remains unclear why ORNs use an anionic current for signal amplification. We have sought to provide clarification on this topic by studying the so far neglected dynamics of $Na^+$, $Ca^{2+}$, $K^+$ and $Cl^-$ in the small space of olfactory cilia during an odorant response. Using computational modeling and simulations we compared the outcomes of signal amplification based on either $Cl^-$ or $Na^+$ currents. We found that amplification produced by $Na^+$ influx instead of a $Cl^-$ efflux is problematic due to several reasons: First, the $Na^+$ current amplitude varies greatly depending on mucosal ion concentration changes. Second, a $Na^+$ current leads to a large increase in the ciliary $Na^+$ concentration during an odorant response. This increase inhibits and even reverses $Ca^{2+}$ clearance by $Na^+/Ca^{2+}/K^+$ exchange, which is essential for response termination. Finally, a $Na^+$ current increases the ciliary osmotic pressure, which could cause swelling to damage the cilia. By contrast, a transduction pathway based on $Cl^-$ efflux circumvents these problems and renders the odorant response robust and reliable.

q-bio.NC↗

arXiv2019

How the Avidity of Polymerase Binding to the -35/-10 Promoter Sites Affects Gene Expression

Although the key promoter elements necessary to drive transcription in Escherichia coli have long been understood, we still cannot predict the behavior of arbitrary novel promoters, hampering our ability to characterize the myriad of sequenced regulatory architectures as well as to design novel synthetic circuits. This work builds upon a beautiful recent experiment by Urtecho et al. who measured the gene expression of over 10,000 promoters spanning all possible combinations of a small set of regulatory elements. Using this data, we demonstrate that a central claim in energy matrix models of gene expression - that each promoter element contributes independently and additively to gene expression - contradicts experimental measurements. We propose that a key missing ingredient from such models is the avidity between the -35 and -10 RNA polymerase binding sites and develop what we call a refined energy matrix model that incorporates this effect. We show that this the refined energy matrix model can characterize the full suite of gene expression data and explore several applications of this framework, namely, how multivalent binding at the -35 and -10 sites can buffer RNAP kinetics against mutations and how promoters that bind overly tightly to RNA polymerase can inhibit gene expression. The success of our approach suggests that avidity represents a key physical principle governing the interaction of RNA polymerase to its promoter.

q-bio.SC↗

arXiv2019

Organization of fast and slow chromatin revealed by single-nucleosome dynamics

Understanding chromatin organization and dynamics is important since they crucially affect DNA functions. In this study, we investigate chromatin dynamics by statistically analyzing single-nucleosome movement in living human cells. Bi-modal nature of the mean squared displacement distribution of nucleosomes allows for a natural categorization of the nucleosomes as fast and slow. Analyses of the nucleosome-nucleosome correlation functions within these categories along with the density of vibrational modes show that the nucleosomes form dynamically correlated fluid regions, i.e., dynamic domains of fast and slow nucleosomes. Perturbed nucleosome dynamics by global histone acetylation or cohesin inactivation indicate that nucleosome-nucleosome interactions along with tethering of chromatin chains organize nucleosomes into fast and slow dynamic domains. A simple polymer model is introduced, which shows the consistency of this dynamic domain picture. Statistical analyses of single-nucleosome movement provide rich information on how chromatin is dynamically organized in a fluid manner in living cells.

cond-mat.soft↗

arXiv2019

How kinesin waits for ATP affects the nucleotide and load dependence of the stepping kinetics

Dimeric molecular motors walk on polar tracks by binding and hydrolyzing one ATP per step. Despite tremendous progress, the waiting state for ATP binding in the well-studied kinesin that walks on microtubule (MT), remains controversial. One experiment suggests that in the waiting state both heads are bound to the MT, while the other shows that ATP binds to the leading head after the partner head detaches. To discriminate between these two scenarios, we developed a theory to calculate accurately several experimentally measurable quantities as a function of ATP concentration and resistive force. In particular, we predict that measurement of the randomness parameter could discriminate between the two scenarios for the waiting state of kinesin, thereby resolving this standing controversy.

q-bio.SC↗

arXiv2022

Sensing the shape of a cell with reaction-diffusion and energy minimization

Some dividing cells sense their shape by becoming polarized along their long axis. Cell polarity is controlled in part by polarity proteins like Rho GTPases cycling between active membrane-bound forms and inactive cytosolic forms, modeled as a "wave-pinning" reaction-diffusion process. Does shape sensing emerge from wave-pinning? We show that wave pinning senses the cell's long axis. Simulating wave-pinning on a curved surface, we find that high-activity domains migrate to peaks and troughs of the surface. For smooth surfaces, a simple rule of minimizing the domain perimeter while keeping its area fixed predicts the final position of the domain and its shape. However, when we introduce roughness to our surfaces, shape sensing can be disrupted, and high-activity domains can become localized to locations other than the global peaks and valleys of the surface. On rough surfaces, the domains of the wave-pinning model are more robust in finding the peaks and troughs than the minimization rule, though both can become trapped in steady states away from the peaks and valleys. We can control the robustness of shape sensing by altering the Rho GTPase diffusivity and the domain size. We also find that the shape sensing properties of cell polarity models can explain how domains localize to curved regions of deformed cells. Our results help to understand the factors that allow cells to sense their shape - and the limits that membrane roughness can place on this process.

physics.bio-ph↗

arXiv2020

Examining the assembly pathways and active microtubule mechanics underlying spindle self-organization

The bipolar organization of the microtubule-based mitotic spindle is essential for the faithful segregation of chromosomes in cell division. Despite our extensive knowledge of genes and proteins, the physical mechanism of how the ensemble of microtubules can assemble into a proper bipolar shape remains elusive. Here, we study the pathways of spindle self-organization using cell-free Xenopus egg extracts and computer-based automated shape analysis. Our microscopy assay allows us to simultaneously record the growth of hundreds of spindles in the bulk cytoplasm and systematically analyze the shape of each structure over the course of self-organization. We find that spindles that are maturing into a bipolar shape take a route that is distinct from those ending up with faulty structures, such as those of a tripolar shape. Moreover, matured structures are highly stable with little occasions of transformation between different shape phenotypes. Visualizing the movement of microtubules further reveals a fraction of microtubules that assemble between extra poles and push the poles apart, suggesting the presence of active extensile force that prevents pole coalescence. Together, we propose that a proper control over the magnitude and location of the extensile, pole-pushing force is crucial for establishing spindle bipolarity while preventing multipolarity.

physics.bio-ph↗

arXiv2026

Diffusive Spreading Across Dynamic Mitochondrial Network Architectures

In eukaryotic cells, mitochondria form networks that range from highly fused interconnected structures to fragmented populations of individual organelles that undergo transient interactions. These structures can be described as temporal networks of physical units, whose dynamic topology is determined by fusion, fission, and motion of the mitochondria through intracellular space. The heterogeneity of the mitochondrial population is governed by diffusive transport and inter-unit exchange of proteins, lipids, ions, and RNA within these networks. We present a unifying framework for the dispersion of material within temporal networks of spatially embedded units that span across a broad connectivity range. Specifically, we consider filling of the networks with a locally produced but globally consumed material, demonstrating that the steady-state content is determined by the balance of timescales for spatial encounter between clusters, local fusion, fission, and diffusive transport within a cluster. As the connectivity increases, filling behavior transitions from three-dimensional spread through a `social network' limited by cluster interactions to low-dimensional transport through a largely stationary `physical network' limited by material diffusivity. We extract parameters for mitochondrial networks in three human cell lines, demonstrating that different cells can access both the social and the physical network regimes. These results provide a quantitative basis for predicting the homogenization of biomolecules through a mitochondrial population. Our framework unifies a variety of temporal network structures into an overarching theory for transport through populations of interacting and interconnected units.

physics.bio-ph↗

arXiv2011

Growth and shortening of microtubules: a two-state model approach

In this study, a two-state mechanochemical model is presented to describe the dynamic instability of microtubules (MTs) in cells. The MTs switches between two states, assembly state and disassembly state. In assembly state, the growth of MTs includes two processes: free GTP-tubulin binding to the tip of protofilament (PF) and conformation change of PF, during which the first tubulin unit which curls outwards is rearranged into MT surface using the energy released from the hydrolysis of GTP in the penultimate tubulin unit. In disassembly state, the shortening of MTs includes also two processes, the release of GDP-tibulin from the tip of PF and one new tubulin unit curls out of the MT surface. Switches between these two states, which are usually called rescue and catastrophe, happen stochastically with external force dependent rates. Using this two-state model with parameters obtained by fitting the recent experimental data, detailed properties of MT growth are obtained, we find that MT is mainly in assembly state, its mean growth velocity increases with external force and GTP-tubulin concentration, MT will shorten in average without external force. To know more about the external force and GTP-tubulin concentration dependent properties of MT growth, and for the sake of the future experimental verification of this two-state model, eleven {\it critical forces} are defined and numerically discussed.

physics.bio-ph↗

arXiv2026

Determining a parabolic-elliptic-elliptic system by boundary observation of its non-negative solutions under chemotaxis background

This paper addresses a profoundly challenging inverse problem that has remained largely unexplored due to its mathematical complexity: the unique identification of all unknown coefficients in a coupled nonlinear system of mixed parabolic-elliptic-elliptic type using only boundary measurements. The system models attraction-repulsion chemotaxis -- an advanced mathematical biology framework for studying sophisticated cellular processes -- yet despite its significant practical importance, the corresponding inverse problem has never been investigated, representing a true frontier in the field. The mixed-type nature of this system introduces significant theoretical difficulties that render conventional methodologies inadequate, demanding fundamental extensions beyond existing techniques developed for simpler, purely parabolic models. Technically, the problem presents formidable obstacles: the coupling between parabolic and elliptic components creates inherent analytical complications, while the nonlinear structure resists standard approaches. From an applied perspective, the biological relevance adds another layer of complexity, as solutions must maintain physical interpretability through non-negativity constraints. Our work provides a complete theoretical framework for this challenging problem, establishing rigorous unique identifiability results that create a one-to-one correspondence between boundary data and the model's parameters. We demonstrate the power of our general theory through a central biological application: the full parameter recovery for an attraction-repulsion chemotaxis model with logistic growth, thus opening new avenues for quantitative analysis in mathematical biology.

math.AP↗

arXiv2018

Unveiling ADP-binding sites and channels in respiratory complexes: Validation of Murburn concept as a holistic explanation for oxidative phosphorylation

Mitochondrial oxidative phosphorylation (mOxPhos) makes ATP, the energy currency of life. Chemiosmosis, a proton centric mechanism, advocates that Complex V harnesses a transmembrane potential (TMP) for ATP synthesis. This perception of cellular respiration requires oxygen to stay tethered at Complex IV (an association inhibited by cyanide) and diffusible reactive oxygen species (DROS) are considered wasteful and toxic products. With new mechanistic insights on heme and flavin enzymes, an oxygen or DROS centric explanation (called murburn concept) was recently proposed for mOxPhos. In the new mechanism, TMP is not directly harnessed, protons are a rate limiting reactant and DROS within matrix serve as the chemical coupling agents that directly link NADH oxidation with ATP synthesis. Herein, we report multiple ADP binding sites and solvent accessible DROS channels in respiratory proteins, which validate the oxygen or DROS centric power generation (ATP synthesis) system in mOxPhos. Since cyanide's heme binding Kd is high (mM), low doses (uM) of cyanide is lethal because cyanide disrupts DROS dynamics in mOxPhos. The critical study also provides comprehensive arguments against Mitchell's and Boyer's explanations and extensive support for murburn concept based holistic perspectives for mOxPhos.

q-bio.SC↗

arXiv2019

The consequence of substrates of large-scale rigidity on actin network tension in adherent cells

There is compelling evidence that substrate stiffness affects cell adhesion as well as cytoskeleton organization and contractile activity. This work was designed to study the cytoskeletal contractile activity of cells plated on microposts of different stiffness using a numerical model simulating the intracellular tension of individual cells. We allowed cells to adhere onto micropost substrates of various rigidities and used experimental traction force data to infer cell contractility using a numerical model. The model discriminates between the influence of substrate stiffness on cell tension and shows that higher substrate stiffness leads to an increase in intracellular tension. The strength of this model is its ability to calculate the mechanical state of each cell in accordance to its individual cytoskeletal structure. This is achieved by regenerating a numerical cytoskeleton based

q-bio.CB↗

arXiv2020

The double dealing of cyclin D1

The cell cycle is tightly regulated by cyclins and their catalytic moieties, the cyclin-dependent kinases (CDKs). Cyclin D1, in association with CDK4/6, acts as a mitogenic sensor and integrates extracellular mitogenic signals and cell cycle progression. When deregulated (overexpressed, accumulated, inappropriately located), cyclin D1 becomes an oncogene and is recognized as a driver of solid tumors and hemopathies. Recent studies on the oncogenic roles of cyclin D1 reported non-canonical functions dependent on the partners of cyclin D1 and its location within tumor cells or tissues. Support for these new functions was provided by various mouse models of oncogenesis. Finally, proteomic and transcriptomic data identified complex cyclin D1 networks. This review focuses on these aspects of cyclin D1 pathophysiology, which may be crucial for targeted therapy.

q-bio.SC↗

arXiv2016

Binding equilibrium and kinetics of membrane-anchored receptors and ligands in cell adhesion: insights from computational model systems and theory

The adhesion of cell membranes is mediated by the binding of membrane-anchored receptor and ligand proteins. In this article, we review recent results from simulations and theory that lead to novel insights on how the binding equilibrium and kinetics of these proteins is affected by the membranes and by the membrane anchoring and molecular properties of the proteins. Simulations and theory both indicate that the binding equilibrium constant K2D and the on- and off-rate constants of anchored receptors and ligands in their 'two-dimensional' (2D) membrane environment strongly depend on the membrane roughness from thermally excited shape fluctuations on nanoscales. Recent theory corroborated by simulations provides a general relation between K2D} and the binding constant K3D of soluble variants of the receptors and ligands that lack the membrane anchors and are free to diffuse in three dimensions (3D).

q-bio.BM↗

arXiv2005

Cellular organization by self-organization : mechanisms and models for Min protein dynamics

We use the oscillating Min proteins of Escherichia coli as a prototype system to illustrate the current state and potential of modeling protein dynamics in space and time. We demonstrate how a theoretical approach has led to striking new insights into the mechanisms of self-organization in bacterial cells and indicate how these ideas may be applicable to more complex structure formation in eukaryotic cells.

q-bio.SC↗

arXiv2011

Classes of fast and specific search mechanisms for proteins on DNA

Problems of search and recognition appear over different scales in biological systems. In this review we focus on the challenges posed by interactions between proteins, in particular transcription factors, and DNA and possible mechanisms which allow for a fast and selective target location. Initially we argue that DNA-binding proteins can be classified, broadly, into three distinct classes which we illustrate using experimental data. Each class calls for a different search process and we discuss the possible application of different search mechanisms proposed over the years to each class. The main thrust of this review is a new mechanism which is based on barrier discrimination. We introduce the model and analyze in detail its consequences. It is shown that this mechanism applies to all classes of transcription factors and can lead to a fast and specific search. Moreover, it is shown that the mechanism has interesting transient features which allow for stability at the target despite rapid binding and unbinding of the transcription factor from the target.

q-bio.BM↗

arXiv2008

Stochastic Dynamical Structure (SDS) of Nonequilibrium Processes in the Absence of Detailed Balance. II: construction of SDS with nonlinear force and multiplicative noise

There is a whole range of emergent phenomena in non-equilibrium behaviors can be well described by a set of stochastic differential equations. Inspired by an insight gained during our study of robustness and stability in phage lambda genetic switch in modern biology, we found that there exists a classification of generic nonequilibrium processes: In the continuous description in terms of stochastic differential equations, there exists four dynamical elements: the potential function $ϕ$, the friction matrix $ S$, the anti-symmetric matrix $ T $, and the noise. The generic feature of absence of detailed balance is then precisely represented by $T$. For dynamical near a fixed point, whether or not it is stable or not, the stochastic dynamics is linear. A rather complete analysis has been carried out (Kwon, Ao, Thouless, cond-mat/0506280; PNAS, {\bf 102} (2005) 13029), referred to as SDS I. One important and persistent question is the existence of a potential function with nonlinear force and with multiplicative noise, with both nice local dynamical and global steady state properties. Here we demonstrate that a dynamical structure built into stochastic differential equation allows us to construct such a global optimization potential function. First, we provide the construction. One of most important ingredient is the generalized Einstein relation. We then present an approximation scheme: The gradient expansion which turns every order into linear matrix equations. The consistent of such methodology with other known stochastic treatments will be discussed in next paper, SDS III; and the explicitly connection to statistical mechanics and thermodynamics will be discussed in a forthcoming paper, SDS IV.

cond-mat.other↗

arXiv2005

Competing Polymerization of Actin Skeleton explains Relation between Network Polarity and Cell Movements

Based on experimental observations it is known that various biological cells exhibit a persistent random walk during migration on flat substrates. The persistent random walk is characterized by `stop-and-go' movements : unidirectional motions over distances of the order of several cell diameter are separated by localized short time erratic movements. Using computer simulations the reasons for this phenomena had been unveiled and shown to be attributed to two antagonistic nucleation processes during the polymerization of the cell's actin cytoskeleton : the (ordinary) spontaneous nucleation and the dendritic nucleation processes. Whereas spontaneous nucleations generate actin filaments growing in different directions and hence create motions in random directions, dendritic nucleations provide a unidirectional growth. Since dendritic growth exhibits stochastic fluctuations, spontaneous nucleation may eventually compete or even dominate, which results in a reorientation of filament growth and hence a new direction of cell motion. The event of reorientation takes place at instants of vanishing polarity of the actin skeleton.

q-bio.SC↗

arXiv2005

Oscillations in molecular motor assemblies

Autonomous oscillations in biological systems may have a biochemical origin or result from an interplay between force-generating and visco-elastic elements. In molecular motor assemblies the force-generating elements are molecular engines and the visco-elastic elements are stiff cytoskeletal polymers. The physical mechanism leading to oscillations depends on the particular architecture of the assembly. Existing models can be grouped into two distinct categories: systems with a delayed force activation and anomalous force-velocity relations. We discuss these systems within phase plane analysis known from the theory of dynamic systems and by adopting methods from control theory, the Nyquist stability criterion.

physics.bio-ph↗