Shenshen Wang

Manipulating the Selection Forces during Affinity Maturation to Generate Cross-Reactive HIV Antibodies

Summary Generation of potent antibodies by a mutation-selection process called affinity maturation is a key component of effective immune responses. Antibodies that protect against highly mutable pathogens must neutralize diverse strains. Developing effective immunization strategies to drive their evolution requires understanding how affinity maturation happens in an enviroment where variants of the same antigen are present. We present an in silico model of affinity maturation driven by antigen variants which reveals that induction of cross-reactive antibodies often occurs with low probability because conflicting selection forces, imposed by different antigen variants, can frustrate affinity maturation. We describe how variables such as temporal pattern of antigen administration influence the outcome of this frustrated evolutionary process. Our calculations predict, and experiments in mice with variant gp120 constructs of the HIV envelope protein confirm, that sequential immunization with antigen variants is preferred over a cocktail for induction of cross-reactive antibodies focused on the shared CD4 binding site epitope.

Active contractility in actomyosin networks

Contractile forces are essential for many developmental processes involving cell shape change and tissue deformation. Recent experiments on reconstituted actomyosin networks, the major component of the contractile machinery, have shown that active contractility occurs above a threshold motor concentration and within a window of cross-link concentration. We present a microscopic dynamic model that incorporates two essential aspects of actomyosin self-organization: the asymmetric load response of individual actin filaments and the correlated motor-driven events mimicking myosin-induced filament sliding. Using computer simulations, we examine how the concentration and susceptibility of motors contribute to their collective behavior and interplay with the network connectivity to regulate macroscopic contractility. Our model is shown to capture the formation and dynamics of contractile structures and agree with the observed dependence of active contractility on microscopic parameters, including the contractility onset. Cooperative action of load-resisting motors in a force-percolating structure integrates local contraction/buckling events into a global contractile state via an active coarsening process, in contrast to the flow transition driven by uncorrelated kicks of susceptible motors.

Communication: Effective temperature and glassy dynamics of active matter

A systematic expansion of the many-body master equation for active matter, in which motors power configurational changes as in the cytoskeleton, is shown to yield a description of the steady state and responses in terms of an effective temperature. The effective temperature depends on the susceptibility of the motors and a Peclet number which measures their strength relative to thermal Brownian diffusion. The analytic prediction is shown to agree with previous numerical simulations and experiments. The mapping also establishes a description of aging in active matter that is also kinetically jammed.

Entanglement tongue and quantum synchronization of disordered oscillators.

We study the synchronization of dissipatively coupled van der Pol oscillators in the quantum limit, when each oscillator is near its quantum ground state. Two quantum oscillators with different frequencies exhibit an entanglement tongue, which is the quantum analog of an Arnold tongue. It means that the oscillators are entangled in steady state when the coupling strength is greater than a critical value, and the critical coupling increases with detuning. An ensemble of many oscillators with random frequencies still exhibits a synchronization phase transition in the quantum limit, and we analytically calculate how the critical coupling depends on the frequency disorder. Our results can be experimentally observed with trapped ions or neutral atoms.

On the spontaneous collective motion of active matter

Spontaneous directed motion, a hallmark of cell biology, is unusual in classical statistical physics. Here we study, using both numerical and analytical methods, organized motion in models of the cytoskeleton in which constituents are driven by energy-consuming motors. Although systems driven by small-step motors are described by an effective temperature and are thus quiescent, at higher order in step size, both homogeneous and inhomogeneous, flowing and oscillating behavior emerges. Motors that respond with a negative susceptibility to imposed forces lead to an apparent negative-temperature system in which beautiful structures form resembling the asters seen in cell division.

Tensegrity and motor-driven effective interactions in a model cytoskeleton.

Actomyosin networks are major structural components of the cell. They provide mechanical integrity and allow dynamic remodeling of eukaryotic cells, self-organizing into the diverse patterns essential for development. We provide a theoretical framework to investigate the intricate interplay between local force generation, network connectivity, and collective action of molecular motors. This framework is capable of accommodating both regular and heterogeneous pattern formation, arrested coarsening and macroscopic contraction in a unified manner. We model the actomyosin system as a motorized cats cradle consisting of a crosslinked network of nonlinear elastic filaments subjected to spatially anti-correlated motor kicks acting on motorized (fibril) crosslinks. The phase diagram suggests there can be arrested phase separation which provides a natural explanation for the aggregation and coalescence of actomyosin condensates. Simulation studies confirm the theoretical picture that a nonequilibrium many-body system driven by correlated motor kicks can behave as if it were at an effective equilibrium, but with modified interactions that account for the correlation of the motor driven motions of the actively bonded nodes. Regular aster patterns are observed both in Brownian dynamics simulations at effective equilibrium and in the complete stochastic simulations. The results show that large-scale contraction requires correlated kicking.

The interplay of nonlinearity and architecture in equilibrium cytoskeletal mechanics

The interplay between cytoskeletal architecture and the nonlinearity of the interactions due to bucklable filaments plays a key role in modulating the cells mechanical stability and affecting its structural rearrangements. We study a model of cytoskeletal structure treating it as an amorphous network of hard centers rigidly cross-linked by nonlinear elastic strings, neglecting the effects of motorization. Using simulations along with a self-consistent phonon method, we show that this minimal model exhibits diverse thermodynamically stable mechanical phases that depend on excluded volume, cross-link concentration, filament length, and stiffness. Within the framework set by the free energy functional formulation and making use of the random first order transition theory of structural glasses, we further estimate the characteristic densities for a kinetic glass transition to occur in this model system. Network connectivity strongly modulates the transition boundaries between various equilibrium phases, as well as the kinetic glass transition density.

Microscopic theory of the glassy dynamics of passive and active network materials.

Signatures of glassy dynamics have been identified experimentally for a rich variety of materials in which molecular networks provide rigidity. Here we present a theoretical framework to study the glassy behavior of both passive and active network materials. We construct a general microscopic network model that incorporates nonlinear elasticity of individual filaments and steric constraints due to crowding. Based on constructive analogies between structural glass forming liquids and random field Ising magnets implemented using a heterogeneous self-consistent phonon method, our scheme provides a microscopic approach to determine the mismatch surface tension and the configurational entropy, which compete in determining the barrier for structural rearrangements within the random first order transition theory of escape from a local energy minimum. The influence of crosslinking on the fragility of inorganic network glass formers is recapitulated by the model. For active network materials, the mapping, which correlates the glassy characteristics to the network architecture and properties of nonequilibrium motor processes, is shown to capture several key experimental observations on the cytoskeleton of living cells: Highly connected tense networks behave as strong glass formers; intense motor action promotes reconfiguration. The fact that our model assuming a negative motor susceptibility predicts the latter suggests that on average the motorized processes in living cells do resist the imposed mechanical load. Our calculations also identify a spinodal point where simultaneously the mismatch penalty vanishes and the mechanical stability of amorphous packing disappears.

Circular-polarization independence of microwave-induced resistance oscillations and the zero-resistance state

The immunity of microwave-induced magneto-resistance oscillations and corresponding zero resistance regions to the direction of (circular) polarization of microwave is studied in this paper. We propose that a spontaneous circular motion of the whole electron fluid would stabilize the system and minimize the polarization sensitivity of the oscillatory DC resistance. Results of a self-consistent calculation capture the qualitative features of the experimental observation.

Optimal Sequential Immunization Can Focus Antibody Responses against Diversity Loss and Distraction.

Affinity maturation is a Darwinian process in which B lymphocytes evolve potent antibodies to encountered antigens and generate immune memory. Highly mutable complex pathogens present an immense antigenic diversity that continues to challenge natural immunity and vaccine design. Induction of broadly neutralizing antibodies (bnAbs) against this diversity by vaccination likely requires multiple exposures to distinct but related antigen variants, and yet how affinity maturation advances under such complex stimulation remains poorly understood. To fill the gap, we present an in silico model of affinity maturation to examine two realistic new aspects pertinent to vaccine development: loss in B cell diversity across successive immunization periods against different variants, and the presence of distracting epitopes that entropically disfavor the evolution of bnAbs. We find these new factors, which introduce additional selection pressures and constraints, significantly influence antibody breadth development, in a way that depends crucially on the temporal pattern of immunization (or selection forces). Curiously, a less diverse B cell seed may even favor the expansion and dominance of cross-reactive clones, but only when conflicting selection forces are presented in series rather than in a mixture. Moreover, the level of frustration due to evolutionary conflict dictates the degree of distraction. We further describe how antigenic histories select evolutionary paths of B cell lineages and determine the predominant mode of antibody responses. Sequential immunization with mutationally distant variants is shown to robustly induce bnAbs that focus on conserved elements of the target epitope, by thwarting strain-specific and distracted lineages. An optimal range of antigen dose underlies a fine balance between efficient adaptation and persistent reaction. These findings provide mechanistic guides to aid in design of vaccine strategies against fast mutating pathogens.