Proceedings of the National Academy of Sciences of the United States of America最新文献

We develop a game-theoretic model of strategic interdependence and tipping in public policy choices and show that the model can be estimated by probit and logit estimators. We test its validity and applicability by using daily data on state-level COVID-19 responses in the United States. Social distancing via shelter-in-place (SIP) strategies and wearing masks emerged as the most effective nonpharmaceutical ways of combatting COVID-19. In the United States, choices about these policies are made by individual states. We develop a game-theoretic model of such choices and test it econometrically, confirming strong interdependence in the implementation of these policies. If enough states engage in social distancing or mask wearing, others will be tipped to follow suit. Policy choices are influenced mainly by the choices of other states, especially those of similar political orientation and to a lesser degree by the number of new COVID-19 cases. The choice of mask-wearing policies is more sensitive to peer choices than the choice of SIP policies, and Republican states are much less likely than Democratic to introduce mask-wearing policies. The choices of policies are influenced more by political than public health considerations. These findings emphasize strategic interdependence in policy choice and offer an analytical framework for these complex dynamics.

Cultural practices perceived to be adaptive-from clearing land for food production to medical innovations-can disseminate quickly through human populations. However, these same practices often have unintended maladaptive effects. A particularly consequential effect is the emergence of diseases. In numerous instances, a cultural change is followed by the appearance of a new pathogen. Here, we develop mathematical models to analyze the population processes through which cultural evolution precipitates the emergence of a new disease. We find that when a risk-bearing cultural practice spreads, emergence can be an unavoidable cost even if a safer alternative practice eventually evolves from the original. Social learning and a fitness advantage associated with the evolving practice drive early disease emergence but the two factors have distinct effects on the time to mutation of the pathogen and significant stochastic variation is observed. For example, a disease can take longer to emerge in a population that adopts the risk-bearing practice quickly than in a population that is slow to transition. Extending the model to explore the effects of an alternative practice evolving from the original, we find a nonmonotonic relationship between relative risk of the two practices and the median time to disease emergence. Our findings contribute to understanding how cultural evolution can shape pathogen evolution and highlight the unpredictability of disease emergence.

Group VIA calcium-independent phospholipase A₂ (iPLA₂) is a member of the PLA₂ superfamily that exhibits calcium-independent activity in contrast to the other two major types, secreted phospholipase A₂ (sPLA₂) and cytosolic phospholipase A₂ (cPLA₂), which both require calcium for their enzymatic activity. Adenosine triphosphate (ATP) has been reported to allosterically activate iPLA₂, and this has now been verified with a lipidomics-based mixed-micelle assay, but its mechanism of action has been unknown. Hydrogen/deuterium exchange mass spectrometry (HDX-MS) was employed to identify ATP interaction peptide regions located within the ankyrin repeat domain at which ATP interacts. Molecular dynamics simulations revealed the mechanism by which ATP binds to its site and the main residues that interact. Site-directed mutagenesis was used to verify the importance of these residues in the role of ATP in regulating iPLA₂ activity. Importantly, calcium was found to abolish the enhancing regulatory function of ATP and to promote the inhibitory activity by calmodulin. Given previous evidence that calcium does not bind directly to iPLA₂, its effect appears to be indirect via association with ATP and/or calmodulin. Using HDX-MS, we found that calmodulin interacts with the N terminus peptide region of iPLA₂ consisting of residues 20 to 28. These two regulatory iPLA₂ sites open the road to the development of potential targets for therapeutic intervention.

Cultural evolution applies evolutionary concepts and tools to explain the change of culture over time. Despite advances in both theoretical and empirical methods, the connections between cultural evolutionary theory and evidence are often vague, limiting progress. Theoretical models influence empirical research but rarely guide data collection and analysis in logical and transparent ways. Theoretical models themselves are often too abstract to apply to specific empirical contexts and guide statistical inference. To help bridge this gap, we outline a quality-assurance computational workflow that starts from generative models of empirical phenomena and logically connects statistical estimates to both theory and real-world explanatory goals. We emphasize and demonstrate validation of the workflow using synthetic data. Using the interplay between conformity, migration, and cultural diversity as a case study, we present coded and repeatable examples of directed acyclic graphs, tailored agent-based simulations, a probabilistic transmission model for longitudinal data, and an approximate Bayesian computation model for cross-sectional data. We discuss the assumptions, opportunities, and pitfalls of different approaches to generative modeling and show how each can be used to improve data analysis depending on the structure of available data and the depth of theoretical understanding. Throughout, we highlight the significance of ethnography and of collecting basic cultural and demographic information about study populations and call for more emphasis on logical and theory-driven workflows as part of science reform.

Investigating microbe-microbe interactions at the single-cell level is critical to unraveling the ecology and dynamics of microbial communities. In many situations, microbes assemble themselves into densely packed multispecies biofilms. The density and complexity pose acute difficulties for visualizing individual cells and analyzing their interactions. Here, we address this problem through an unconventional application of expansion microscopy, which allows for the "decrowding" of individual bacterial cells within a multispecies community. Expansion microscopy generally has been carried out under isotropic expansion conditions and used as a resolution-enhancing method. In our variation of expansion microscopy, we carry out expansion under heterotropic conditions; that is, we expand the space between bacterial cells but not the space within individual cells. The separation of individual bacterial cells from each other reflects the competition between the expansion force pulling them apart and the adhesion force holding them together. We employed heterotropic expansion microscopy to study the relative strength of adhesion in model biofilm communities. These included mono- and dual-species Streptococcus biofilms and a three-species synthetic community (Fusobacterium nucleatum, Streptococcus mutans, and Streptococcus sanguinis) under conditions that facilitated interspecies coaggregation. Using adhesion mutants, we investigated the interplay between F. nucleatum outer membrane protein RadD and different Streptococcus species. We also examined the Schaalia-TM7 epibiont association. Quantitative proximity analysis was used to evaluate the separation of individual microbial members. Our study demonstrates that heterotropic expansion microscopy can "decrowd" dense biofilm communities, improve visualization of individual bacterial members, and enable analysis of microbe-microbe adhesive interactions at the single-cell level.

Persistent pain frequently precipitates the development of anxiety disorders, yet the underlying mechanisms are not fully understood. In this study, we employed a mouse model that simulates trigeminal neuralgia and observed a marked reduction in the activity of GABAergic neurons in the lateral habenula (LHb), a critical region for modulating pain and anxiety. We utilized precise optogenetic and chemogenetic techniques to modulate these neurons, which significantly alleviated behaviors associated with pain and anxiety. Our investigations revealed an inhibitory pathway from the LHb GABAergic neurons to the posterior paraventricular thalamus. Activation of this pathway primarily mitigated pain-related behaviors, with minimal effects on anxiety. Conversely, interactions between GABAergic and glutamatergic neurons within the LHb were essential in alleviating both pain and anxiety following trigeminal nerve damage. Additionally, we identified that β-sitosterol interacts directly with LHb GABAergic neurons via the estrogen receptor α, providing dual therapeutic effects for both pain and anxiety. These findings highlight the critical role of reduced GABAergic neuronal activity in the LHb in the intersection of pain and anxiety, pointing to promising therapeutic possibilities.

Advances in singe-particle cryo-electron microscopy (cryo-EM) have made it possible to solve the structures of numerous Family A and Family B G protein-coupled receptors (GPCRs) in complex with G proteins and arrestins, as well as several Family C GPCRs. Determination of these structures has been facilitated by the presence of large extramembrane components (such as G protein, arrestin, or Venus flytrap domains) in these complexes that aid in particle alignment during the processing of the cryo-EM data. In contrast, determination of the inactive state structure of Family A GPCRs is more challenging due to the relatively small size of the seven transmembrane domain (7TM) and to the surrounding detergent micelle that, in the absence of other features, make particle alignment impossible. Here, we describe an alternative protein engineering strategy where the heterodimeric protein calcineurin is fused to a GPCR by three points of attachment, the cytoplasmic ends of TM5, TM6, and TM7. This three-point attachment provides a more rigid link with the GPCR transmembrane domain that facilitates particle alignment during data processing, allowing us to determine the structures of the β₂ adrenergic receptor (β₂AR) in the apo, antagonist-bound, and agonist-bound states. We expect that this fusion strategy may have broad application in cryo-EM structural determination of other Family A GPCRs.

Many enveloped viruses bud from the plasma membrane that is tightly associated with a dense and thick actin cortex. This actin network represents a significant challenge for membrane deformation and scission, and how it is remodeled during the late steps of the viral cycle is largely unknown. Using superresolution microscopy, we show that HIV-1 buds in areas of the plasma membrane with low cortical F-actin levels. We find that the cellular oxidoreductase MICAL1 locally depolymerizes actin at budding sites to promote HIV-1 budding and release. Upon MICAL1 depletion, F-actin abnormally remains at viral budding sites, incompletely budded viruses accumulate at the plasma membrane and viral release is impaired. Remarkably, normal viral release can be restored in MICAL1-depleted cells by inhibiting Arp2/3-dependent branched actin networks. Mechanistically, we find that MICAL1 directly disassembles branched-actin networks and controls the timely recruitment of the Endosomal Sorting Complexes Required for Transport scission machinery during viral budding. In addition, the MICAL1 activator Rab35 is recruited at budding sites, functions in the same pathway as MICAL1, and is also required for viral release. This work reveals a role for oxidoreduction in triggering local actin depolymerization to control HIV-1 budding, a mechanism that may be widely used by other viruses. The debranching activity of MICAL1 could be involved beyond viral budding in various other cellular functions requiring local plasma membrane deformation.