Thioredoxin is a metabolic rheostat controlling regulatory B cells.

Metabolic programming is important for B cell fate, but the bioenergetic requirement for regulatory B (Breg) cell differentiation and function is unknown. Here we show that Breg cell differentiation, unlike non-Breg cells, relies on mitochondrial electron transport and homeostatic levels of reactive oxygen species (ROS). Single-cell RNA sequencing analysis revealed that TXN, encoding the metabolic redox protein thioredoxin (Trx), is highly expressed by Breg cells, unlike Trx inhibitor TXNIP which was downregulated. Pharmacological inhibition or gene silencing of TXN resulted in mitochondrial membrane depolarization and increased ROS levels, selectively suppressing Breg cell differentiation and function while favoring pro-inflammatory B cell differentiation. Patients with systemic lupus erythematosus (SLE), characterized by Breg cell deficiencies, present with B cell mitochondrial membrane depolarization, elevated ROS and fewer Trx+ B cells. Exogenous Trx stimulation restored Breg cells and mitochondrial membrane polarization in SLE B cells to healthy B cell levels, indicating Trx insufficiency underlies Breg cell impairment in patients with SLE.

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.

sciCSR infers B cell state transition and predicts class-switch recombination dynamics using single-cell transcriptomic data.

Class-switch recombination (CSR) is an integral part of B cell maturation. Here we present sciCSR (pronounced 'scissor', single-cell inference of class-switch recombination), a computational pipeline that analyzes CSR events and dynamics of B cells from single-cell RNA sequencing (scRNA-seq) experiments. Validated on both simulated and real data, sciCSR re-analyzes scRNA-seq alignments to differentiate productive heavy-chain immunoglobulin transcripts from germline 'sterile' transcripts. From a snapshot of B cell scRNA-seq data, a Markov state model is built to infer the dynamics and direction of CSR. Applying sciCSR on severe acute respiratory syndrome coronavirus 2 vaccination time-course scRNA-seq data, we observe that sciCSR predicts, using data from an earlier time point in the collected time-course, the isotype distribution of B cell receptor repertoires of subsequent time points with high accuracy (cosine similarity ~0.9). Using processes specific to B cells, sciCSR identifies transitions that are often missed by conventional RNA velocity analyses and can reveal insights into the dynamics of B cell CSR during immune response.

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.

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.

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.

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.

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.

Multi-Omics Reveals Mechanisms of Partial Modulation of COVID-19 Dysregulation by Glucocorticoid Treatment.

Treatments for COVID-19 infections have improved dramatically since the beginning of the pandemic, and glucocorticoids have been a key tool in improving mortality rates. The UK's National Institute for Health and Care Excellence guidance is for treatment to be targeted only at those requiring oxygen supplementation, however, and the interactions between glucocorticoids and COVID-19 are not completely understood. In this work, a multi-omic analysis of 98 inpatient-recruited participants was performed by quantitative metabolomics (using targeted liquid chromatography-mass spectrometry) and data-independent acquisition proteomics. Both 'omics datasets were analysed for statistically significant features and pathways differentiating participants whose treatment regimens did or did not include glucocorticoids. Metabolomic differences in glucocorticoid-treated patients included the modulation of cortisol and bile acid concentrations in serum, but no alleviation of serum dyslipidemia or increased amino acid concentrations (including tyrosine and arginine) in the glucocorticoid-treated cohort relative to the untreated cohort. Proteomic pathway analysis indicated neutrophil and platelet degranulation as influenced by glucocorticoid treatment. These results are in keeping with the key role of platelet-associated pathways and neutrophils in COVID-19 pathogenesis and provide opportunity for further understanding of glucocorticoid action. The findings also, however, highlight that glucocorticoids are not fully effective across the wide range of 'omics dysregulation caused by COVID-19 infections.

Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.

Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.

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.

Whole genome sequencing identifies an allele responsible for clear vs. turbid plaque morphology in a Mycobacteriophage.

BACKGROUND: Whole genome sequencing promises to revolutionize our ability to link genotypic and phenotypic variation in a wide range of model and non-model species. RESULTS: Here we describe the isolation and characterization of a novel mycobacteriophage named BGlluviae that grows on Mycobacterium smegmatis mc2155. BGlluviae normally produces turbid plaques but a spontaneous clear plaque was also recovered. The genomic DNA from pure populations of the BGlluviae phage and the clear plaque mutant were sequenced. A single substitution, at amino acid 54 (I to T), in the immunity repressor protein resulted in a clear plaque phenotype. CONCLUSIONS: This substitution is predicted to be located at the subunit interaction interface of the repressor protein, and thus prevents the establishment of lysogeny.

BRepertoire: a user-friendly web server for analysing antibody repertoire data.

Antibody repertoire analysis by high throughput sequencing is now widely used, but a persisting challenge is enabling immunologists to explore their data to discover discriminating repertoire features for their own particular investigations. Computational methods are necessary for large-scale evaluation of antibody properties. We have developed BRepertoire, a suite of user-friendly web-based software tools for large-scale statistical analyses of repertoire data. The software is able to use data preprocessed by IMGT, and performs statistical and comparative analyses with versatile plotting options. BRepertoire has been designed to operate in various modes, for example analysing sequence-specific V(D)J gene usage, discerning physico-chemical properties of the CDR regions and clustering of clonotypes. Those analyses are performed on the fly by a number of R packages and are deployed by a shiny web platform. The user can download the analysed data in different table formats and save the generated plots as image files ready for publication. We believe BRepertoire to be a versatile analytical tool that complements experimental studies of immune repertoires. To illustrate the server's functionality, we show use cases including differential gene usage in a vaccination dataset and analysis of CDR3H properties in old and young individuals. The server is accessible under http://mabra.biomed.kcl.ac.uk/BRepertoire.

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.

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.

Half the story: Thermal effects on within-host infectious disease progression in a warming climate.

Immune defense is temperature dependent in cold-blooded vertebrates (CBVs) and thus directly impacted by global warming. We examined whether immunity and within-host infectious disease progression are altered in CBVs under realistic climate warming in a seasonal mid-latitude setting. Going further, we also examined how large thermal effects are in relation to the effects of other environmental variation in such a setting (critical to our ability to project infectious disease dynamics from thermal relationships alone). We employed the three-spined stickleback and three ecologically relevant parasite infections as a "wild" model. To generate a realistic climatic warming scenario we used naturalistic outdoors mesocosms with precise temperature control. We also conducted laboratory experiments to estimate thermal effects on immunity and within-host infectious disease progression under controlled conditions. As experimental readouts we measured disease progression for the parasites and expression in 14 immune-associated genes (providing insight into immunophenotypic responses). Our mesocosm experiment demonstrated significant perturbation due to modest warming (+2°C), altering the magnitude and phenology of disease. Our laboratory experiments demonstrated substantial thermal effects. Prevailing thermal effects were more important than lagged thermal effects and disease progression increased or decreased in severity with increasing temperature in an infection-specific way. Combining laboratory-determined thermal effects with our mesocosm data, we used inverse modeling to partition seasonal variation in Saprolegnia disease progression into a thermal effect and a latent immunocompetence effect (driven by nonthermal environmental variation and correlating with immune gene expression). The immunocompetence effect was large, accounting for at least as much variation in Saprolegnia disease as the thermal effect. This suggests that managers of CBV populations in variable environments may not be able to reliably project infectious disease risk from thermal data alone. Nevertheless, such projections would be improved by primarily considering prevailing thermal effects in the case of within-host disease and by incorporating validated measures of immunocompetence.

Delusional Infestation: Perspectives from Scottish Dermatologists and a 10-year Case Series from a Single Centre.

Perceptions of the clinical management of delusional infestation (DI) were compared with clinical outcomes in this 10-year case series from a single centre in Dundee, UK. An online questionnaire (survey-monkey, a TM brand of online survey available for free for basic use) was sent to Scottish Dermatologists to gauge their opinions and confidence in the management of DI. Also, a retrospective review of medical case notes of patients seen by dermatologists in one institution was undertaken and clinical outcomes were reported by patients' general practitioners (GP). The survey showed that 61% of responding dermatologists encountered 1-5 cases of DI per year. Twenty-four percent respondees were 'confident' in managing patients with DI, 54% were 'somewhat confident'. Forty-seven patients (62% female, 70% single) were seen over the 10 years; 43% brought a self-collected specimen to clinic, 68% of patients had a psychiatric comorbidity, 23% of patients had primary DI and 11/47 (23%) were seen by a psychiatrist. Clinical outcomes as rated by patients' GPs were reasonable or good in 2/3 patients. A poor outcome was seen in 12 patients and associated with chronic pain in 50% (p < 0.01) and psychiatric comorbidity in 100% (p < 0.01). We conclude that good outcomes can be achieved in some patients with DI without psychiatric input and without psychoactive treatment.

An immunological marker of tolerance to infection in wild rodents.

Hosts are likely to respond to parasitic infections by a combination of resistance (expulsion of pathogens) and tolerance (active mitigation of pathology). Of these strategies, the basis of tolerance in animal hosts is relatively poorly understood, with especially little known about how tolerance is manifested in natural populations. We monitored a natural population of field voles using longitudinal and cross-sectional sampling modes and taking measurements on body condition, infection, immune gene expression, and survival. Using analyses stratified by life history stage, we demonstrate a pattern of tolerance to macroparasites in mature compared to immature males. In comparison to immature males, mature males resisted infection less and instead increased investment in body condition in response to accumulating burdens, but at the expense of reduced reproductive effort. We identified expression of the transcription factor Gata3 (a mediator of Th2 immunity) as an immunological biomarker of this tolerance response. Time series data for individual animals suggested that macroparasite infections gave rise to increased expression of Gata3, which gave rise to improved body condition and enhanced survival as hosts aged. These findings provide a clear and unexpected insight into tolerance responses (and their life history sequelae) in a natural vertebrate population. The demonstration that such responses (potentially promoting parasite transmission) can move from resistance to tolerance through the course of an individual's lifetime emphasises the need to incorporate them into our understanding of the dynamics and risk of infection in the natural environment. Moreover, the identification of Gata3 as a marker of tolerance to macroparasites raises important new questions regarding the role of Th2 immunity and the mechanistic nature of the tolerance response itself. A more manipulative, experimental approach is likely to be valuable in elaborating this further.

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.

Seasonal immunoregulation in a naturally-occurring vertebrate.

BACKGROUND: Fishes show seasonal patterns of immunity, but such phenomena are imperfectly understood in vertebrates generally, even in humans and mice. As these seasonal patterns may link to infectious disease risk and individual condition, the nature of their control has real practical implications. Here we characterize seasonal dynamics in the expression of conserved vertebrate immunity genes in a naturally-occurring piscine model, the three-spined stickleback. RESULTS: We made genome-wide measurements (RNAseq) of whole-fish mRNA pools (n = 36) at the end of summer and winter in contrasting habitats (riverine and lacustrine) and focussed on common trends to filter habitat-specific from overarching temporal responses. We corroborated this analysis with targeted year-round whole-fish gene expression (Q-PCR) studies in a different year (n = 478). We also considered seasonal tissue-specific expression (6 tissues) (n = 15) at a third contrasting (euryhaline) locality by Q-PCR, further validating the generality of the patterns seen in whole fish analyses. Extremes of season were the dominant predictor of immune expression (compared to sex, ontogeny or habitat). Signatures of adaptive immunity were elevated in late summer. In contrast, late winter was accompanied by signatures of innate immunity (including IL-1 signalling and non-classical complement activity) and modulated toll-like receptor signalling. Negative regulators of T-cell activity were prominent amongst winter-biased genes, suggesting that adaptive immunity is actively down-regulated during winter rather than passively tracking ambient temperature. Network analyses identified a small set of immune genes that might lie close to a regulatory axis. These genes acted as hubs linking summer-biased adaptive pathways, winter-biased innate pathways and other organismal processes, including growth, metabolic dynamics and responses to stress and temperature. Seasonal change was most pronounced in the gill, which contains a considerable concentration of T-cell activity in the stickleback. CONCLUSIONS: Our results suggest major and predictable seasonal re-adjustments of immunity. Further consideration should be given to the effects of such responses in seasonally-occurring disease.