Epistatic hotspots organize antibody fitness landscape and boost evolvability.

The course of evolution is strongly shaped by interaction between mutations. Such epistasis can yield rugged sequence-function maps and constrain the availability of adaptive paths. While theoretical intuition is often built on global statistics of large, homogeneous model landscapes, mutagenesis measurements necessarily probe a limited neighborhood of a reference genotype.

Physical extraction of antigen and information.

To respond and adapt, cells use surface receptors to sense environmental cues. While biochemical signal processing inside the cell is studied in depth, less is known about how physical processes during cell-cell contact impact signal acquisition. New experiments found that fast-evolving immune B cells in germinal centers (GCs) apply force to acquire antigen clusters prior to internalization, suggesting adaptive benefits of physical information extraction.

Long-term retention of antigens in germinal centers is controlled by the spatial organization of the follicular dendritic cell network.

Germinal centers (GCs) require sustained availability of antigens to promote antibody affinity maturation against pathogens and vaccines. A key source of antigens for GC B cells are immune complexes (ICs) displayed on follicular dendritic cells (FDCs). Here we show that FDC spatial organization regulates antigen dynamics in the GC.

Modeling and Simulation of the Hysteretic Behavior of Concrete under Cyclic Tension-Compression Using the Smeared Crack Approach.

Concrete structures under wind and earthquake loads will experience tensile and compressive stress reversals. It is very important to accurately reproduce the hysteretic behavior and energy dissipation of concrete materials under cyclic tension-compression for the safety evaluation of concrete structures. A hysteretic model for concrete under cyclic tension-compression is proposed in the framework of smeared crack theory.

Multiple phase transitions shape biodiversity of a migrating population.

In a wide variety of natural systems, closely related microbial strains coexist stably, resulting in high levels of fine-scale biodiversity. However, the mechanisms that stabilize this coexistence are not fully understood. Spatial heterogeneity is one common stabilizing mechanism, but the rate at which organisms disperse throughout the heterogeneous environment may strongly impact the stabilizing effect that heterogeneity can provide.

Work-Related Factors Associated With the Pelvic Floor Dysfunction Among a Sample of Female Nurses in China.

Background: Female nurses are a high-risk group for pelvic floor dysfunction (PFD). Predictors of female nurses' PFD among work-related factors are not well known. The aim of this study was to investigate the prevalence of PFD and its association with workplace conditions among female nurses in China.

Immune cells use active tugging forces to distinguish affinity and accelerate evolution.

Cells are known to exert forces to sense their physical surroundings for guidance of motion and fate decisions. Here, we propose that cells might do mechanical work to drive their own evolution, taking inspiration from the adaptive immune system. Growing evidence indicates that immune B cells-capable of rapid Darwinian evolution-use cytoskeletal forces to actively extract antigens from other cells' surfaces.

Verifying Negative Sentences.

In the long history of psycholinguistic research on verifying negative sentences, an often-reported finding is that participants take longer to correctly judge negative sentences true than false, while being faster to judge their positive counterparts true (e.g. Clark & Chase, Cogn Psychol 3(3):472-517, 1972; Carpenter & Just, Psychol Rev 82(1):45-73, 1975).

Coevolutionary transitions emerging from flexible molecular recognition and eco-evolutionary feedback.

Highly mutable viruses evolve to evade host immunity that exerts selective pressure and adapts to viral dynamics. Here, we provide a framework for identifying key determinants of the mode and fate of viral-immune coevolution by linking molecular recognition and eco-evolutionary dynamics. We find that conservation level and initial diversity of antigen jointly determine the timing and efficacy of narrow and broad antibody responses, which in turn control the transition between viral persistence, clearance, and rebound.

Roadmap on biology in time varying environments.

Biological organisms experience constantly changing environments, from sudden changes in physiology brought about by feeding, to the regular rising and setting of the Sun, to ecological changes over evolutionary timescales. Living organisms have evolved to thrive in this changing world but the general principles by which organisms shape and are shaped by time varying environments remain elusive. Our understanding is particularly poor in the intermediate regime with no separation of timescales, where the environment changes on the same timescale as the physiological or evolutionary response.

Shaping Polyclonal Responses via Antigen-Mediated Antibody Interference.

Broadly neutralizing antibodies (bnAbs) recognize conserved features of rapidly mutating pathogens and confer universal protection, but they emerge rarely in natural infection. Increasing evidence indicates that seemingly passive antibodies may interfere with natural selection of B cells. Yet, how such interference modulates polyclonal responses is unknown.

Aging-induced fragility of the immune system.

The adaptive and innate branches of the vertebrate immune system work in close collaboration to protect organisms from harmful pathogens. As an organism ages its immune system undergoes immunosenescence, characterized by declined performance or malfunction in either immune branch, which can lead to disease and death. In this study we develop a mathematical framework of coupled innate and adaptive immune responses, namely the integrated immune branch (IIB) model.

Tuning environmental timescales to evolve and maintain generalists.

Natural environments can present diverse challenges, but some genotypes remain fit across many environments. Such "generalists" can be hard to evolve, outcompeted by specialists fitter in any particular environment. Here, inspired by the search for broadly neutralizing antibodies during B cell affinity maturation, we demonstrate that environmental changes on an intermediate timescale can reliably evolve generalists, even when faster or slower environmental changes are unable to do so.

Evolving generalists in switching rugged landscapes.

Evolving systems, be it an antibody repertoire in the face of mutating pathogens or a microbial population exposed to varied antibiotics, constantly search for adaptive solutions in time-varying fitness landscapes. Generalists refer to genotypes that remain fit across diverse selective pressures; while multi-drug resistant microbes are undesired yet prevalent, broadly-neutralizing antibodies are much wanted but rare. However, little is known about under what conditions such generalists with a high capacity to adapt can be efficiently discovered by evolution.

Active Tuning of Synaptic Patterns Enhances Immune Discrimination.

Immune cells learn about their antigenic targets using tactile sense: a self-organized motif named immunological synapse forms between an immune cell and an antigen-presenting cell (APC) during recognition. Via synapses, immune cells apply mechanical pulling forces to selectively extract antigen (Ag) from APCs. Curiously, depending on its stage of development, a B lymphocyte exhibits distinct synaptic patterns and uses force at different strength and timing, which appears to strongly impact its ability to distinguish Ag affinities.

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.

Effects of dietary protein and energy levels on digestive enzyme activities and electrolyte composition in the small intestinal fluid of geese.

The present study was conducted to evaluate the effects of dietary protein and energy levels on digestive enzymes and electrolyte composition in jejunum of geese. A 3×3 factorial and completely randomized design was adopted with three protein levels and three energy levels. The experiment included four replicates for each treatment, and three geese for each replicate.

Manipulating the selection forces during affinity maturation to generate cross-reactive HIV antibodies.

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 environment where variants of the same antigen are present.

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.

Active patterning and asymmetric transport in a model actomyosin network.

Cytoskeletal networks, which are essentially motor-filament assemblies, play a major role in many developmental processes involving structural remodeling and shape changes. These are achieved by nonequilibrium self-organization processes that generate functional patterns and drive intracellular transport. We construct a minimal physical model that incorporates the coupling between nonlinear elastic responses of individual filaments and force-dependent motor action.

The effects of somatic hypermutation on neutralization and binding in the PGT121 family of broadly neutralizing HIV antibodies.

Broadly neutralizing HIV antibodies (bnAbs) are typically highly somatically mutated, raising doubts as to whether they can be elicited by vaccination. We used 454 sequencing and designed a novel phylogenetic method to model lineage evolution of the bnAbs PGT121-134 and found a positive correlation between the level of somatic hypermutation (SHM) and the development of neutralization breadth and potency. Strikingly, putative intermediates were characterized that show approximately half the mutation level of PGT121-134 but were still capable of neutralizing roughly 40-80% of PGT121-134 sensitive viruses in a 74-virus panel at median titers between 15- and 3-fold higher than PGT121-134.

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.

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.