A computational model for the cancer field effect.

Introduction: The Cancer Field Effect describes an area of pre-cancerous cells that results from continued exposure to carcinogens. Cells in the cancer field can easily develop into cancer. Removal of the main tumor mass might leave the cancer field behind, increasing risk of recurrence.

Personalized Virus Load Curves for Acute Viral Infections.

We introduce an explicit function that describes virus-load curves on a patient-specific level. This function is based on simple and intuitive model parameters. It allows virus load analysis of acute viral infections without solving a full virus load dynamic model.

HSP70 chaperones RNA-free TDP-43 into anisotropic intranuclear liquid spherical shells.

The RNA binding protein TDP-43 forms intranuclear or cytoplasmic aggregates in age-related neurodegenerative diseases. In this study, we found that RNA binding-deficient TDP-43 (produced by neurodegeneration-causing mutations or posttranslational acetylation in its RNA recognition motifs) drove TDP-43 demixing into intranuclear liquid spherical shells with liquid cores. These droplets, which we named "anisosomes", have shells that exhibit birefringence, thus indicating liquid crystal formation.

Spatial heterogeneity of the cytosol revealed by machine learning-based 3D particle tracking.

The spatial structure and physical properties of the cytosol are not well understood. Measurements of the material state of the cytosol are challenging due to its spatial and temporal heterogeneity. Recent development of genetically encoded multimeric nanoparticles (GEMs) has opened up study of the cytosol at the length scales of multiprotein complexes (20-60 nm).

LPS-binding IgG arrests actively motile Salmonella Typhimurium in gastrointestinal mucus.

The gastrointestinal (GI) mucosa is coated with a continuously secreted mucus layer that serves as the first line of defense against invading enteric bacteria. We have previously shown that antigen-specific immunoglobulin G (IgG) can immobilize viruses in both human airway and genital mucus secretions through multiple low-affinity bonds between the array of virion-bound IgG and mucins, thereby facilitating their rapid elimination from mucosal surfaces and preventing mucosal transmission. Nevertheless, it remains unclear whether weak IgG-mucin crosslinks could reinforce the mucus barrier against the permeation of bacteria driven by active flagella beating, or in predominantly MUC2 mucus gel.

Limited processivity of single motors improves overall transport flux of self-assembled motor-cargo complexes.

Single kinesin molecular motors can processively move along a microtubule (MT) a few micrometers on average before dissociating. However, cellular length scales over which transport occurs are several hundred microns and more. Why seemingly unreliable motors are used to transport cellular cargo remains poorly understood.

Modeling Barrier Properties of Intestinal Mucus Reinforced with IgG and Secretory IgA against Motile Bacteria.

The gastrointestinal (GI) tract is lined with a layer of viscoelastic mucus gel, characterized by a dense network of entangled and cross-linked mucins together with an abundance of antibodies (Ab). Secretory IgA (sIgA), the predominant Ab isotype in the GI tract, is a dimeric molecule with 4 antigen-binding domains capable of inducing efficient clumping of bacteria, or agglutination. IgG, another common Ab at mucosal surfaces, can cross-link individual viruses to the mucin mesh through multiple weak bonds between IgG-Fc and mucins, a process termed muco-trapping.

Hydrodynamics of transient cell-cell contact: The role of membrane permeability and active protrusion length.

In many biological settings, two or more cells come into physical contact to form a cell-cell interface. In some cases, the cell-cell contact must be transient, forming on timescales of seconds. One example is offered by the T cell, an immune cell which must attach to the surface of other cells in order to decipher information about disease.

Engineering Polymer-Binding Bispecific Antibodies for Enhanced Pretargeted Delivery of Nanoparticles to Mucus-Covered Epithelium.

Mucus represents a major barrier to sustained and targeted drug delivery to mucosal epithelium. Ideal drug carriers should not only rapidly diffuse across mucus, but also bind the epithelium. Unfortunately, ligand-conjugated particles often exhibit poor penetration across mucus.

Partial demixing of RNA-protein complexes leads to intradroplet patterning in phase-separated biological condensates.

An emerging mechanism for intracellular organization is liquid-liquid phase separation (LLPS). Found in both the nucleus and the cytoplasm, liquidlike droplets condense to create compartments that are thought to promote and inhibit specific biochemistry. In this work, a multiphase, Cahn-Hilliard diffuse interface model is used to examine RNA-protein interactions driving LLPS.

Convolutional neural networks automate detection for tracking of submicron-scale particles in 2D and 3D.

Particle tracking is a powerful biophysical tool that requires conversion of large video files into position time series, i.e., traces of the species of interest for data analysis.

ZMapp Reinforces the Airway Mucosal Barrier Against Ebola Virus.

Filoviruses, including Ebola, have the potential to be transmitted via virus-laden droplets deposited onto mucus membranes. Protecting against such emerging pathogens will require understanding how they may transmit at mucosal surfaces and developing strategies to reinforce the airway mucus barrier. Here, we prepared Ebola pseudovirus (with Zaire strain glycoproteins) and used high-resolution multiple-particle tracking to track the motions of hundreds of individual pseudoviruses in fresh and undiluted human airway mucus isolated from extubated endotracheal tubes.

Control of septin filament flexibility and bundling by subunit composition and nucleotide interactions.

Septins self-assemble into heteromeric rods and filaments to act as scaffolds and modulate membrane properties. How cells tune the biophysical properties of septin filaments to control filament flexibility and length, and in turn the size, shape, and position of higher-order septin structures, is not well understood. We examined how rod composition and nucleotide availability influence physical properties of septins such as annealing, fragmentation, bundling, and bending.

Technological strategies to estimate and control diffusive passage times through the mucus barrier in mucosal drug delivery.

In mucosal drug delivery, two design goals are desirable: 1) insure drug passage through the mucosal barrier to the epithelium prior to drug removal from the respective organ via mucus clearance; and 2) design carrier particles to achieve a prescribed arrival time and drug uptake schedule at the epithelium. Both goals are achievable if one can control "one-sided" diffusive passage times of drug carrier particles: from deposition at the mucus interface, through the mucosal barrier, to the epithelium. The passage time distribution must be, with high confidence, shorter than the timescales of mucus clearance to maximize drug uptake.

A blueprint for robust crosslinking of mobile species in biogels with weakly adhesive molecular anchors.

Biopolymeric matrices can impede transport of nanoparticulates and pathogens by entropic or direct adhesive interactions, or by harnessing "third-party" molecular anchors to crosslink nanoparticulates to matrix constituents. The trapping potency of anchors is dictated by association rates and affinities to both nanoparticulates and matrix; the popular dogma is that long-lived, high-affinity bonds to both species facilitate optimal trapping. Here we present a contrasting paradigm combining experimental evidence (using IgG antibodies and Matrigel®), a theoretical framework (based on multiple timescale analysis), and computational modeling.

Uniform asymptotic approximation of diffusion to a small target: Generalized reaction models.

The diffusion of a reactant to a binding target plays a key role in many biological processes. The reaction radius at which the reactant and target may interact is often a small parameter relative to the diameter of the domain in which the reactant diffuses. We develop uniform in time asymptotic expansions in the reaction radius of the full solution to the corresponding diffusion equations for two separate reactant-target interaction mechanisms: the Doi or volume reactivity model and the Smoluchowski-Collins-Kimball partial-absorption surface reactivity model.

The Binding Site Barrier Elicited by Tumor-Associated Fibroblasts Interferes Disposition of Nanoparticles in Stroma-Vessel Type Tumors.

The binding site barrier (BSB) was originally proposed to describe the binding behavior of antibodies to cells peripheral to blood vessels, preventing their further penetration into the tumors. Yet, it is revisited herein to describe the intratumoral cellular disposition of nanoparticles (NPs). Specifically, the BSB limits NP diffusion and results in unintended internalization of NPs by stroma cells localized near blood vessels.

First-Passage Time to Clear the Way for Receptor-Ligand Binding in a Crowded Environment.

Certain biological reactions, such as receptor-ligand binding at cell-cell interfaces and macromolecules binding to biopolymers, require many smaller molecules crowding a reaction site to be cleared. Examples include the T-cell interface, a key player in immunological information processing. Diffusion sets a limit for such cavitation to occur spontaneously, thereby defining a time scale below which active mechanisms must take over.

Path integrals and large deviations in stochastic hybrid systems.

We construct a path-integral representation of solutions to a stochastic hybrid system, consisting of one or more continuous variables evolving according to a piecewise-deterministic dynamics. The differential equations for the continuous variables are coupled to a set of discrete variables that satisfy a continuous-time Markov process, which means that the differential equations are only valid between jumps in the discrete variables. Examples of stochastic hybrid systems arise in biophysical models of stochastic ion channels, motor-driven intracellular transport, gene networks, and stochastic neural networks.

Effects of moderate noise on a limit cycle oscillator: counterrotation and bistability.

The effects of noise on the dynamics of nonlinear systems is known to lead to many counterintuitive behaviors. Using simple planar limit cycle oscillators, we show that the addition of moderate noise leads to qualitatively different dynamics. In particular, the system can appear bistable, rotate in the opposite direction of the deterministic limit cycle, or cease oscillating altogether.

Stochastic hybrid model of spontaneous dendritic NMDA spikes.

Following recent advances in imaging techniques and methods of dendritic stimulation, active voltage spikes have been observed in thin dendritic branches of excitatory pyramidal neurons, where the majority of synapses occur. The generation of these dendritic spikes involves both Na(+) ion channels and M-methyl-D-aspartate receptor (NMDAR) channels. During strong stimulation of a thin dendrite, the resulting high levels of glutamate, the main excitatory neurotransmitter in the central nervous system and an NMDA agonist, modify the current-voltage (I-V) characteristics of an NMDAR so that it behaves like a voltage-gated Na(+) channel.

Breakdown of fast-slow analysis in an excitable system with channel noise.

We consider a stochastic version of an excitable system based on the Morris-Lecar model of a neuron, in which the noise originates from stochastic sodium and potassium ion channels opening and closing. One can analyze neural excitability in the deterministic model by using a separation of time scales involving a fast voltage variable and a slow recovery variable, which represents the fraction of open potassium channels. In the stochastic setting, spontaneous excitation is initiated by ion channel noise.

Metastable behavior in Markov processes with internal states.

A perturbation framework is developed to analyze metastable behavior in stochastic processes with random internal and external states. The process is assumed to be under weak noise conditions, and the case where the deterministic limit is bistable is considered. A general analytical approximation is derived for the stationary probability density and the mean switching time between metastable states, which includes the pre exponential factor.

Uniform asymptotic approximation of diffusion to a small target.

The problem of the time required for a diffusing molecule, within a large bounded domain, to first locate a small target is prevalent in biological modeling. Here we study this problem for a small spherical target. We develop uniform in time asymptotic expansions in the target radius of the solution to the corresponding diffusion equation.