The role of uncertainty and negative feedback loops in the evolution of induced immune defenses.

Organisms use constitutive or induced defenses against pathogens and other external threats. Constitutive defenses are constantly on, whereas induced defenses are activated when needed. Each of these strategies has costs and benefits, which can affect the type of defense that evolves in response to pathogens. In addition, induced defenses are usually regulated by multiple negative feedback mechanisms that prevent overactivation of the immune response. However, it is unclear how negative feedback affects the costs, benefits, and evolution of induced responses. To address this gap, we developed a mechanistic model of the well-characterized Drosophila melanogaster immune signaling network that includes three separate mechanisms of negative feedback as a representative of the widespread phenomenon of muti-level regulation of induced responses. We show that, under stochastic fly-bacteria encounters, an induced defense is favored when bacterial encounters are rare or uncertain, but in ways that depend on the bacterial proliferation rate. Our model also predicts that the specific negative regulators that optimize the induced response depend on the bacterial proliferation rate, linking negative feedback mechanisms to the factors that favor induction.

Resolving selfish and spiteful interdependent conflict.

Interdependence occurs when individuals have a stake in the success or failure of others, such that the outcomes experienced by one individual also generate costs or benefits for others. Discussion on this topic has typically focused on positive interdependence (where gains for one individual result in gains for another) and on the consequences for cooperation. However, interdependence can also be negative (where gains for one individual result in losses for another), which can spark conflict. In this article, we explain when negative interdependence is likely to arise and, crucially, the role played by (mis)perception in shaping an individual's understanding of their interdependent relationships. We argue that, owing to the difficulty in accurately perceiving interdependence with others, individuals might often be mistaken about the stake they hold in each other's outcomes, which can spark needless, resolvable forms of conflict. We then discuss when and how reducing misperceptions can help to resolve such conflicts. We argue that a key mechanism for resolving interdependent conflict, along with better sources of exogenous information, is to reduce reliance on heuristics such as stereotypes when assessing the nature of our interdependent relationships.

The distorting effects of producer strategies: Why engagement does not reveal consumer preferences for misinformation.

A great deal of empirical research has examined who falls for misinformation and why. Here, we introduce a formal game-theoretic model of engagement with news stories that captures the strategic interplay between (mis)information consumers and producers. A key insight from the model is that observed patterns of engagement do not necessarily reflect the preferences of consumers. This is because producers seeking to promote misinformation can use strategies that lead moderately inattentive readers to engage more with false stories than true ones-even when readers prefer more accurate over less accurate information. We then empirically test people's preferences for accuracy in the news. In three studies, we find that people strongly prefer to click and share news they perceive as more accurate-both in a general population sample, and in a sample of users recruited through Twitter who had actually shared links to misinformation sites online. Despite this preference for accurate news-and consistent with the predictions of our model-we find markedly different engagement patterns for articles from misinformation versus mainstream news sites. Using 1,000 headlines from 20 misinformation and 20 mainstream news sites, we compare Facebook engagement data with 20,000 accuracy ratings collected in a survey experiment. Engagement with a headline is negatively correlated with perceived accuracy for misinformation sites, but positively correlated with perceived accuracy for mainstream sites. Taken together, these theoretical and empirical results suggest that consumer preferences cannot be straightforwardly inferred from empirical patterns of engagement.

Eco-evolutionary trade-offs in the dynamics of prion strain competition.

Prion and prion-like molecules are a type of self-replicating aggregate protein that have been implicated in a variety of neurodegenerative diseases. Over recent decades, the molecular dynamics of prions have been characterized both empirically and through mathematical models, providing insights into the epidemiology of prion diseases and the impact of prions on the evolution of cellular processes. At the same time, a variety of evidence indicates that prions are themselves capable of a form of evolution, in which changes to their structure that impact their rate of growth or fragmentation are replicated, making such changes subject to natural selection. Here we study the role of such selection in shaping the characteristics of prions under the nucleated polymerization model (NPM). We show that fragmentation rates evolve to an evolutionary stable value which balances rapid reproduction of PrPSc aggregates with the need to produce stable polymers. We further show that this evolved fragmentation rate differs in general from the rate that optimizes transmission between cells. We find that under the NPM, prions that are both evolutionary stable and optimized for transmission have a characteristic length of three times the critical length below which they become unstable. Finally, we study the dynamics of inter-cellular competition between strains, and show that the eco-evolutionary trade-off between intra- and inter-cellular competition favours coexistence.

Group reciprocity and the evolution of stereotyping.

Stereotypes are generalized beliefs about groups of people, which are used to make decisions and judgements about them. Although such heuristics can be useful when decisions must be made quickly, or when information is lacking, they can also serve as the basis for prejudice and discrimination. In this paper, we study the evolution of stereotypes through group reciprocity. We characterize the warmth of a stereotype as the willingness to cooperate with an individual based solely on the identity of the group they belong to. We show that when stereotype groups are large, such group reciprocity is less likely to evolve, and stereotypes tend to be negative. We also show that, even when stereotypes are broadly positive, individuals are often overly pessimistic about the willingness of those they stereotype to cooperate. We then show that the tendency for stereotyping itself to evolve is driven by the costs of cognition, so that more people are stereotyped with greater coarseness as costs increase. Finally we show that extrinsic 'shocks', in which the benefits of cooperation are suddenly reduced, can cause stereotype warmth and judgement bias to turn sharply negative, consistent with the view that economic and other crises are drivers of out-group animosity.

Inequality, identity, and partisanship: How redistribution can stem the tide of mass polarization.

The form of political polarization where citizens develop strongly negative attitudes toward out-party members and policies has become increasingly prominent across many democracies. Economic hardship and social inequality, as well as intergroup and racial conflict, have been identified as important contributing factors to this phenomenon known as "affective polarization." Research shows that partisan animosities are exacerbated when these interests and identities become aligned with existing party cleavages. In this paper, we use a model of cultural evolution to study how these forces combine to generate and maintain affective political polarization. We show that economic events can drive both affective polarization and the sorting of group identities along party lines, which, in turn, can magnify the effects of underlying inequality between those groups. But, on a more optimistic note, we show that sufficiently high levels of wealth redistribution through the provision of public goods can counteract this feedback and limit the rise of polarization. We test some of our key theoretical predictions using survey data on intergroup polarization, sorting of racial groups, and affective polarization in the United States over the past 50 y.

Radical and Ionic Mechanisms in Rearrangements of o-Tolyl Aryl Ethers and Amines Initiated by the Grubbs-Stoltz Reagent, Et3SiH/KOtBu.

Rearrangements of o-tolyl aryl ethers, amines, and sulfides with the Grubbs-Stoltz reagent (Et3SiH + KOtBu) were recently announced, in which the ethers were converted to o-hydroxydiarylmethanes, while the (o-tol)(Ar)NH amines were transformed into dihydroacridines. Radical mechanisms were proposed, based on prior evidence for triethylsilyl radicals in this reagent system. A detailed computational investigation of the rearrangements of the aryl tolyl ethers now instead supports an anionic Truce-Smiles rearrangement, where the initial benzyl anion can be formed by either of two pathways: (i) direct deprotonation of the tolyl methyl group under basic conditions or (ii) electron transfer to an initially formed benzyl radical. By contrast, the rearrangements of o-tolyl aryl amines depend on the nature of the amine. Secondary amines undergo deprotonation of the N-H followed by a radical rearrangement, to form dihydroacridines, while tertiary amines form both dihydroacridines and diarylmethanes through radical and/or anionic pathways. Overall, this study highlights the competition between the reactive intermediates formed by the Et3SiH/KOtBu system.

The natural selection of good science.

Scientists in some fields are concerned that many published results are false. Recent models predict selection for false positives as the inevitable result of pressure to publish, even when scientists are penalized for publications that fail to replicate. We model the cultural evolution of research practices when laboratories are allowed to expend effort on theory, enabling them, at a cost, to identify hypotheses that are more likely to be true, before empirical testing. Theory can restore high effort in research practice and suppress false positives to a technical minimum, even without replication. The mere ability to choose between two sets of hypotheses, one with greater prior chance of being correct, promotes better science than can be achieved with effortless access to the set of stronger hypotheses. Combining theory and replication can have synergistic effects. On the basis of our analysis, we propose four simple recommendations to promote good science.

Polarization under rising inequality and economic decline.

Social and political polarization is an important source of conflict in many societies. Understanding its causes has become a priority of scholars across disciplines. We demonstrate that shifts in socialization strategies analogous to political polarization can arise as a locally beneficial response to both rising wealth inequality and economic decline. In many contexts, interaction with diverse out-groups confers benefits from innovation and exploration greater than those that arise from interacting exclusively with a homogeneous in-group. However, when the economic environment favors risk aversion, a strategy of seeking lower-risk in-group interactions can be important to maintaining individual solvency. Our model shows that under conditions of economic decline or increasing inequality, some members of the population benefit from adopting a risk-averse, in-group favoring strategy. Moreover, we show that such in-group polarization can spread rapidly to the whole population and persist even when the conditions that produced it have reversed.

Influence of pilot hole diameter in cancellous screw fixation in a reduced density animal bone model.

BACKGROUND: Screw fixation in osteoporotic bone is clinically challenging. Screw failure rates are growing due to an increasing prevalence of osteoporosis. To address this, biomechanical models are needed to recreate the bone clinically encountered alongside the development of new operative techniques. The first aim of this study was to test whether the use of a smaller than recommended pilot-hole diameter improved pull-out strength for cancellous screws, with the second aim to create a model of low-density porcine bone for biomechanical testing. METHODS: Thirty porcine tibiae were cut into transverse metaphyseal sections of 20 mm thickness. Bone density was altered using 0.15 M Hydrochloric acid, and measured and pre- and post-demineralisation using HRµCT. Seventy-two screw areas were randomised to either 2.5 mm or 1.5 mm pilot holes and to either be normal or reduced density. Maximum axial pull-out strength was measured. FINDINGS: Demineralisation reduced bone density by 12% (p < 0.0001) and 11% (p < 0.0001) for 2.5 mm and 1.5 mm pilot hole diameters respectively. Pull-out strength reduced by 50% (p = 0.0001) and 44% (p < 0.0001) following demineralisation for both 2.5 mm and 1.5 mm pilot hole diameters. Pull-out strength increased by 51% (p = 0.0008) when inserting screws into 1.5 mm pilot holes in low density bone, and by 28% (p = 0.027) in normal bone. INTERPRETATION: Porcine bone can be demineralised to model low density cancellous bone. This novel model showed that pullout force is significantly reduced in lower density screw holes, but that this reduction can be mitigated by reducing pilot hole diameter for cancellous screws.

Information gerrymandering and undemocratic decisions.

People must integrate disparate sources of information when making decisions, especially in social contexts. But information does not always flow freely. It can be constrained by social networks1-3 and distorted by zealots and automated bots4. Here we develop a voter game as a model system to study information flow in collective decisions. Players are assigned to competing groups (parties) and placed on an 'influence network' that determines whose voting intentions each player can observe. Players are incentivized to vote according to partisan interest, but also to coordinate their vote with the entire group. Our mathematical analysis uncovers a phenomenon that we call information gerrymandering: the structure of the influence network can sway the vote outcome towards one party, even when both parties have equal sizes and each player has the same influence. A small number of zealots, when strategically placed on the influence network, can also induce information gerrymandering and thereby bias vote outcomes. We confirm the predicted effects of information gerrymandering in social network experiments with n = 2,520 human subjects. Furthermore, we identify extensive information gerrymandering in real-world influence networks, including online political discussions leading up to the US federal elections, and in historical patterns of bill co-sponsorship in the US Congress and European legislatures. Our analysis provides an account of the vulnerabilities of collective decision-making to systematic distortion by restricted information flow. Our analysis also highlights a group-level social dilemma: information gerrymandering can enable one party to sway decisions in its favour, but when multiple parties engage in gerrymandering the group loses its ability to reach consensus and remains trapped in deadlock.

Sexual antagonism drives the displacement of polymorphism across gene regulatory cascades.

Males and females have different reproductive roles and are often subject to contrasting selection pressures. This sexual antagonism can lead, at a given locus, to different alleles being favoured in each sex and, consequently, to genetic variation being maintained in a population. Although the presence of sexually antagonistic (SA) polymorphisms has been documented across a range of species, their evolutionary dynamics remain poorly understood. Here, we study SA selection on gene expression, which is fundamental to sexual dimorphism, via the evolution of regulatory binding sites. We show that for sites longer than 1 nucleotide, expression polymorphism is maintained only when intermediate expression levels are deleterious to both sexes. We then show that, in a regulatory cascade, expression polymorphism tends to become displaced over evolutionary time from the target of SA selection to upstream regulators. Our results have consequences for understanding the evolution of sexual dimorphism, and provide specific empirical predictions for the regulatory architecture of genes under SA selection.

Evolution of empathetic moral evaluation.

Social norms can promote cooperation by assigning reputations to individuals based on their past actions. A good reputation indicates that an individual is likely to reciprocate. A large body of research has established norms of moral assessment that promote cooperation, assuming reputations are objective. But without a centralized institution to provide objective evaluation, opinions about an individual's reputation may differ across a population. In this setting we study the role of empathy-the capacity to form moral evaluations from another person's perspective. We show that empathy tends to foster cooperation by reducing the rate of unjustified defection. The norms of moral evaluation previously considered most socially beneficial depend on high levels of empathy, whereas different norms maximize social welfare in populations incapable of empathy. Finally, we show that empathy itself can evolve through social contagion. We conclude that a capacity for empathy is a key component for sustaining cooperation in societies.

Evolutionary consequences of behavioral diversity.

Iterated games provide a framework to describe social interactions among groups of individuals. This body of work has focused primarily on individuals who face a simple binary choice, such as "cooperate" or "defect." Real individuals, however, can exhibit behavioral diversity, varying their input to a social interaction both qualitatively and quantitatively. Here we explore how access to a greater diversity of behavioral choices impacts the evolution of social dynamics in populations. We show that, in public goods games, some simple strategies that choose between only two possible actions can resist invasion by all multichoice invaders, even while engaging in relatively little punishment. More generally, access to a larger repertoire of behavioral choices results in a more "rugged" fitness landscape, with populations able to stabilize cooperation at multiple levels of investment. As a result, increased behavioral choice facilitates cooperation when returns on investments are low, but it hinders cooperation when returns on investments are high. Finally, we analyze iterated rock-paper-scissors games, the nontransitive payoff structure of which means that unilateral control is difficult to achieve. Despite this, we find that a large proportion of multichoice strategies can invade and resist invasion by single-choice strategies-so that even well-mixed populations will tend to evolve and maintain behavioral diversity.

Small groups and long memories promote cooperation.

Complex social behaviors lie at the heart of many of the challenges facing evolutionary biology, sociology, economics, and beyond. For evolutionary biologists the question is often how group behaviors such as collective action, or decision making that accounts for memories of past experience, can emerge and persist in an evolving system. Evolutionary game theory provides a framework for formalizing these questions and admitting them to rigorous study. Here we develop such a framework to study the evolution of sustained collective action in multi-player public-goods games, in which players have arbitrarily long memories of prior rounds of play and can react to their experience in an arbitrary way. We construct a coordinate system for memory-m strategies in iterated n-player games that permits us to characterize all cooperative strategies that resist invasion by any mutant strategy, and stabilize cooperative behavior. We show that, especially when groups are small, longer-memory strategies make cooperation easier to evolve, by increasing the number of ways to stabilize cooperation. We also explore the co-evolution of behavior and memory. We find that even when memory has a cost, longer-memory strategies often evolve, which in turn drives the evolution of cooperation, even when the benefits for cooperation are low.

Collapse of cooperation in evolving games.

Game theory provides a quantitative framework for analyzing the behavior of rational agents. The Iterated Prisoner's Dilemma in particular has become a standard model for studying cooperation and cheating, with cooperation often emerging as a robust outcome in evolving populations. Here we extend evolutionary game theory by allowing players' payoffs as well as their strategies to evolve in response to selection on heritable mutations. In nature, many organisms engage in mutually beneficial interactions and individuals may seek to change the ratio of risk to reward for cooperation by altering the resources they commit to cooperative interactions. To study this, we construct a general framework for the coevolution of strategies and payoffs in arbitrary iterated games. We show that, when there is a tradeoff between the benefits and costs of cooperation, coevolution often leads to a dramatic loss of cooperation in the Iterated Prisoner's Dilemma. The collapse of cooperation is so extreme that the average payoff in a population can decline even as the potential reward for mutual cooperation increases. Depending upon the form of tradeoffs, evolution may even move away from the Iterated Prisoner's Dilemma game altogether. Our work offers a new perspective on the Prisoner's Dilemma and its predictions for cooperation in natural populations; and it provides a general framework to understand the coevolution of strategies and payoffs in iterated interactions.

From extortion to generosity, evolution in the Iterated Prisoner's Dilemma.

Recent work has revealed a new class of "zero-determinant" (ZD) strategies for iterated, two-player games. ZD strategies allow a player to unilaterally enforce a linear relationship between her score and her opponent's score, and thus to achieve an unusual degree of control over both players' long-term payoffs. Although originally conceived in the context of classical two-player game theory, ZD strategies also have consequences in evolving populations of players. Here, we explore the evolutionary prospects for ZD strategies in the Iterated Prisoner's Dilemma (IPD). Several recent studies have focused on the evolution of "extortion strategies," a subset of ZD strategies, and have found them to be unsuccessful in populations. Nevertheless, we identify a different subset of ZD strategies, called "generous ZD strategies," that forgive defecting opponents but nonetheless dominate in evolving populations. For all but the smallest population sizes, generous ZD strategies are not only robust to being replaced by other strategies but can selectively replace any noncooperative ZD strategy. Generous strategies can be generalized beyond the space of ZD strategies, and they remain robust to invasion. When evolution occurs on the full set of all IPD strategies, selection disproportionately favors these generous strategies. In some regimes, generous strategies outperform even the most successful of the well-known IPD strategies, including win-stay-lose-shift.

The evolution of complex gene regulation by low-specificity binding sites.

Requirements for gene regulation vary widely both within and among species. Some genes are constitutively expressed, whereas other genes require complex regulatory control. Transcriptional regulation is often controlled by a module of multiple transcription factor binding sites that, in combination, mediate the expression of a target gene. Here, we study how such regulatory modules evolve in response to natural selection. Using a population-genetic model, we show that complex regulatory modules which contain a larger number of binding sites must employ binding motifs that are less specific, on average, compared with smaller regulatory modules. This effect is extremely general, and it holds regardless of the selected binding logic that a module experiences. We attribute this phenomenon to the inability of stabilizing selection to maintain highly specific sites in large regulatory modules. Our analysis helps to explain broad empirical trends in the Saccharomyces cerevisiae regulatory network: those genes with a greater number of distinct transcriptional regulators feature less-specific binding motifs, compared with genes with fewer regulators. Our results also help to explain empirical trends in module size and motif specificity across species, ranging from prokaryotes to single-cellular and multi-cellular eukaryotes.

Under-dominance constrains the evolution of negative autoregulation in diploids.

Regulatory networks have evolved to allow gene expression to rapidly track changes in the environment as well as to buffer perturbations and maintain cellular homeostasis in the absence of change. Theoretical work and empirical investigation in Escherichia coli have shown that negative autoregulation confers both rapid response times and reduced intrinsic noise, which is reflected in the fact that almost half of Escherichia coli transcription factors are negatively autoregulated. However, negative autoregulation is rare amongst the transcription factors of Saccharomyces cerevisiae. This difference is surprising because E. coli and S. cerevisiae otherwise have similar profiles of network motifs. In this study we investigate regulatory interactions amongst the transcription factors of Drosophila melanogaster and humans, and show that they have a similar dearth of negative autoregulation to that seen in S. cerevisiae. We then present a model demonstrating that this striking difference in the noise reduction strategies used amongst species can be explained by constraints on the evolution of negative autoregulation in diploids. We show that regulatory interactions between pairs of homologous genes within the same cell can lead to under-dominance--mutations which result in stronger autoregulation, and decrease noise in homozygotes, paradoxically can cause increased noise in heterozygotes. This severely limits a diploid's ability to evolve negative autoregulation as a noise reduction mechanism. Our work offers a simple and general explanation for a previously unexplained difference between the regulatory architectures of E. coli and yeast, Drosophila and humans. It also demonstrates that the effects of diploidy in gene networks can have counter-intuitive consequences that may profoundly influence the course of evolution.

The population genetics of cooperative gene regulation.

BACKGROUND: Changes in gene regulatory networks drive the evolution of phenotypic diversity both within and between species. Rewiring of transcriptional networks is achieved either by changes to transcription factor binding sites or by changes to the physical interactions among transcription factor proteins. It has been suggested that the evolution of cooperative binding among factors can facilitate the adaptive rewiring of a regulatory network. RESULTS: We use a population-genetic model to explore when cooperative binding of transcription factors is favored by evolution, and what effects cooperativity then has on the adaptive re-writing of regulatory networks. We consider a pair of transcription factors that regulate multiple targets and overlap in the sets of target genes they regulate. We show that, under stabilising selection, cooperative binding between the transcription factors is favoured provided the amount of overlap between their target genes exceeds a threshold. The value of this threshold depends on several population-genetic factors: strength of selection on binding sites, cost of pleiotropy associated with protein-protein interactions, rates of mutation and population size. Once it is established, we find that cooperative binding of transcription factors significantly accelerates the adaptive rewiring of transcriptional networks under positive selection. We compare our qualitative predictions to systematic data on Saccharomyces cerevisiae transcription factors, their binding sites, and their protein-protein interactions. CONCLUSIONS: Our study reveals a rich set of evolutionary dynamics driven by a tradeoff between the beneficial effects of cooperative binding at targets shared by a pair of factors, and the detrimental effects of cooperative binding for non-shared targets. We find that cooperative regulation will evolve when transcription factors share a sufficient proportion of their target genes. These findings help to explain empirical pattens in datasets of transcription factors in Saccharomyces cerevisiae and, they suggest that changes to physical interactions between transcription factors can play a critical role in the evolution of gene regulatory networks.