Evolution, Medicine, and Public Health

Background In a retrospective online survey, we assessed the extent to which people with symptomatic hypermobility are at risk of Long COVID with a high degree of post-exertional symptom exacerbation, a form of Long COVID similar to myalgic encephalomyelitis. Methods Participants were 1,816 adults with prior COVID-19 infection; 19.4% reported Long COVID, defined as symptoms persisting [≥]3 months. Survey measures identified Long COVID with high post-exertional symptom exacerbation, generalized joint hypermobility (GJH), extreme hypermobility, and a pre-COVID orthostatic/neurocognitive symptom burden (ONS profile). Logistic regression assessed whether ONS profile and hypermobility, together defined as symptomatic hypermobility, were associated with increased risk of Long COVID with post-exertional symptom exacerbation. Results In the full sample, both extreme hypermobility (OR 3.15, 95 % CI 2.00-4.95) and an ONS profile pre-COVID (OR 3.29, 95% CI 2.34-4.61) were strongly predictive of Long COVID with high post-exertional symptom exacerbation. These effects were cumulative, leading to an OR of 9.46 (95% CI 4.93-18.17) for people with both conditions. People who both had an ONS profile pre-COVID and had generalized joint hypermobility also had a higher risk of Long COVID with high post-exertional symptom exacerbation (OR 5.54, 95% CI 3.51-8.75). Conclusions In this dataset, people with symptomatic hypermobility were at high risk of Long COVID with high levels of post-exertional symptom exacerbation. Further research is needed to understand the biological mechanisms of viral-onset illness to promote more effective and targeted treatments tailored to the disease pathways shared by groups of individuals with common vulnerabilities.

Maximum lifespan varies more than 100-fold across vertebrates, yet within each species aging emerges as a coordinated syndrome spanning metabolism, immunity, endocrine signaling, cognition, and regeneration. We propose the Metabolic Scope Theory of Aging (MSTA), which treats longevity as the time required to exhaust mitochondrial bioenergetic reserve rather than as a consequence of resting metabolic rate alone. The framework decomposes lifespan into three physical axes: Scope, the reserve capacity that buffers cumulative damage; Stability, the resistance of mtDNA-linked OXPHOS architecture to erosion; and Pace, the temperature-dependent kinetics of lesion accumulation. Using body mass as a Scope proxy, mtDNA GC content as a Stability proxy, and body temperature as Pace, the resulting Scope-Stability-Pace relation, lnMLS = lnBM + {beta} GC% -{gamma} Tb + c, explains [~]69% of mammalian maximum-lifespan variance across 379 species. Cross-class comparisons reinforce the same constraint structure: birds offset high thermal Pace through elevated mtDNA Stability, and the SSP temperature coefficient derived from mammals matches the temperature dependence of lifespan observed in ectotherms. The framework further connects comparative lifespan scaling to Gompertz-like mortality acceleration through progressive reserve erosion and threshold crossing. Mechanistically, MSTA models cumulative mtDNA-linked damage as rising impedance within OXPHOS. Increasing internal resistance drives mitochondria toward a high-redox-pressure, low-current regime that preserves basal ATP while restricting NAD+ regeneration, CoQ acceptor availability, and {Delta}p-dependent work. The earliest failure is therefore not energetic collapse but loss of regenerative scope: NAD+-gated TCA flux, aspartate and nucleotide synthesis, one-carbon metabolism, and redox-buffered repair become progressively harder to sustain, and diverse age- related pathologies emerge as tissue-specific projections of this shared upstream constraint. MSTA separates a reversible, operational impedance (redox poise, membrane potential, endocrine tone) from a fixed, informational one (accumulated mtDNA damage) that sets the hard ceiling on lifespan. Because the informational layer cannot be reversed by regulatory means, the framework predicts that until therapies can directly restore mitochondrial conductance, interventions will be most effective when they relieve redox pressure or bypass constrained biosynthetic gates.

Hosts defend themselves against parasites through resistance (reducing parasite burden) and tolerance (reducing the fitness cost of infection without affecting parasites). This distinction has important evolutionary implications: resistance is predicted to maintain polymorphism while tolerance tends to fix, and only resistance is expected to provoke parasite counter-adaptation. The reaction-norm framework, which infers tolerance from the slope of host fitness regressed on parasite burden, assumes that a shallow slope reflects parasite-independent host protection. We test this assumption using a within-host model in two variants: microparasites (Model 1, with within-host replication) and macroparasites (Model 2, without). Sublethal immunity impairs the host-exploitation rate of the parasite, reducing both growth and per-parasite virulence without killing them. We show that this generates systematic slope differences among host genotypes that the framework interprets as variation in tolerance. Furthermore, the ranking of slopes across genotypes reverses between linear and sigmoidal damage functions: under linear damage, the strongest immune responder appears most tolerant; under sigmoidal damage, the weakest responder does. Decomposition of the damage reduction shows that virulence reduction accounts for the majority of the effect across both model variants. Thus, the reaction-norm slope cannot determine whether host fitness is maintained by parasite-independent tissue protection or by sublethal impairment of parasites.

Viral populations can experience a dramatic reduction in population size and genetic diversity during transmission between donor and recipient hosts. Transmission bottlenecks can therefore decrease the evolutionary potential of viral populations, slowing adaptation by increasing the strength of genetic drift and decreasing the strength of selection. Recent barcoded influenza experiments in guinea pigs showed that recipient animals receive a diverse viral inoculum but lose most of that diversity within one to two days. The resulting bottleneck therefore arises not at physical transfer but during early viral growth in the recipient. We develop a branching-process framework to quantify how much of this loss follows from stochasticity in early growth alone. Each transmitted lineage is treated as an independent stochastic process governed by measurable viral parameters. We recover these parameters from viral growth rates estimated from observed viral load. A residual filter for each animal then captures any additional loss imposed by the recipient host. Applied to twenty-four recipient animals, the model reveals two distinct groups. For roughly half of the animals, the stochastic extinction during early growth already accounts for the observed loss. For the remaining animals, the additional host filter is severe. Only about one in a hundred free virions pass through. This decomposition offers a quantitative entry point for future work on immune contributions to transmission bottlenecks.

The basic reproduction number R0 confounds pathogen biology with adaptive human contact behavior. Earlier epidemiological--economic theory predicted a forward-looking behavioral contact response but could not test it in the absence of appropriate behavioral data. Using directly measured mobility as an observable proxy for contact, we (i) estimate the behavioral response function directly from data; (ii) show that the biology/behavior decomposition and hence the behavioral correction to R0 is not identified from an epidemic trajectory, the apparent constant-contact R0 being one endpoint of an observational-equivalence class that fits the factual curve identically yet diverges under counterfactual; and (iii) characterize that divergence ("what R0 deletes") as state-dependent, unimodal in counterfactual severity and vanishing when behavior saturates. We then show that, across US jurisdictions, the correction is empirically bounded because risk-responsiveness and behavioral non-saturation are confounded (r=-0.57, n=51): where behavior could compensate, it was already maximal, and where it was not maximal it did not respond. What R0 deletes is thus real and structurally characterizable yet empirically modest here, for reasons the framework itself supplies.

Oxytocin and vasopressin are endogenous bioactive peptides with conserved roles in reproduction and, more recently recognized, in peripheral lipid metabolism. Whether this signaling system also shapes how reproduction declines with age has not been tested in any animal. Here we show that in C. elegans, the oxytocin/vasopressin-like neuropeptide nematocin restrains reproductive output as animals reach mid-life. Nematocin and its two receptors are produced throughout adult life and peak as reproduction begins to wane. Animals lacking receptor signaling produce more offspring in mid-life, an improvement that reflects better egg quality and fertilization rather than improved embryo survival. This benefit is accompanied by changes in intestinal fat metabolism, the worm's equivalent of liver and adipose tissue: nematocin normally limits the activity of a fatty-acid desaturase that is otherwise induced by mating, and it shapes how much yolk reaches developing eggs. The two receptors act through separate routes, one tuning intestinal fat metabolism and the other controlling yolk delivery to the egg. Together, these findings reveal nematocin as a regulator of the intestinal metabolic environment across reproductive age, mirroring the recently described oxytocin-hepatocyte-adipocyte lipid axis in mammals and implicate this conserved signaling system in the coordination of maternal investment during reproductive aging.

Filoviruses, including the likely bat-borne Ebola virus (EBOV) and Marburg virus (MARV), cause severe hemorrhagic fevers in humans. The 2013-2016 EBOV outbreak caused >11,000 human fatalities in Guinea, Liberia, and Sierra Leone. Nearby countries, including Ghana, have been under sampled for filoviruses relative to West African countries where large outbreaks have occurred. While there have been no reported EBOV disease cases in Ghana, there were two fatal MARV disease cases in 2022, suggesting that at least one filovirus is circulating in the country. In this study, we investigated filovirus circulation in fruit bats and humans in Ghana. We leveraged an extensive serological dataset collected from multiple fruit bat species (n = 6,874) and humans (n = 1,300) across a decade in Ghana (2010-2020), including both rural and urban regions. We observed evidence of MARV circulation in Rousettus aegyptiacus bats, a presumed reservoir, as well as occasional seropositivity in sympatric bat species, suggesting that these other bats are incidental, dead-end hosts. Multivariate analyses suggested that multiple, partially cross-reactive filoviruses are circulating among fruit bats in Ghana. Finally, people who reported spending time in caves and hunting bats had higher serological reactivity against EBOV and MARV relative to individuals with no direct bat exposure, indicating possible undetected filovirus spillover at the bat-human interface in Ghana.

Why male primates invest in costly behaviours producing public goods remains debated, with two leading explanations, paternal care and reputation-based partner choice (RBPC). Using long-term data from four groups of wild vervet monkeys, we tested: (1) whether males show a bias in four protective "male services" (predator alarm calling, participation in between-group conflicts, leading river crossings and sentinelling); (2) which males contribute most; and (3) whether service provision predicts mating success during the mating season. We confirmed a male bias in all services. Consistent with the paternal care hypothesis, contributions were positively associated with past mating success, independently of rank, although potential fathers did not contribute more than non-fathers. Among non-fathers, service provision varied with rank, suggesting that newly immigrated males adjust their behaviour according to competitive state. Crucially, variation in alarm calling and between-group conflicts predicted future mating success, with between-group conflict emerging as the strongest and most consistent predictor of mating success across years and within mating seasons, whereas rank, tenure and social integration added little explanatory power. In contrast, sentinelling and leading river crossings did not reliably translate into mating benefits. Our findings indicate that male services are shaped by multiple selective pressures operating across different male career stages and that some forms of public goods provision function as signals of quality and cooperativeness to females. By directly linking cooperative investment to mating outcomes in a wild primate, this study provides rare empirical support for reputation-based partner choice beyond humans and highlights female choice as a potentially important force in the evolution of cooperation.

BackgroundLyme borreliosis is a common tick-borne disease in Europe caused by spirochetes of the Borrelia burgdorferi sensu lato complex, including Borrelia afzelii, which is maintained in nature through interactions with rodent reservoir hosts. These spirochetes have evolved several surface proteins to manipulate rodent host immunity, some of which remain polymorphic in Borrelia populations. Among these proteins, OspE, which binds the host complement-regulating factor CFH to evade destruction by complement, is one of the most variable. Yet, what evolutionary forces maintain this polymorphism is not well understood. Motivated by a recent discovery of CFH polymorphism in the bank vole (Clethrionomys glareolus), the main reservoir host of B. afzelii, we hypothesized that the polymorphism is maintained by host-parasite coevolution involving specific associations between host and parasite genetic variants. MethodsWe analyzed associations between bank vole CFH alleles and B. afzelii OspE variants across three datasets sampled in Poland. Selection acting on OspE was evaluated using omegaMap. Host-pathogen genotype associations were tested using partial redundancy analysis (RDA), and co-structure was assessed using co-correspondence analysis (CoCA). ResultsWe found that OspE evolves under positive selection, however, we found no evidence for an association between OspE and host CFH variants at the individual level based on RDA or at the population level based on CoCA. ConclusionsDespite evidence of positive selection acting on OspE, we found no support for specific genetic matching between B. afzelii and its bank vole host at the CFH-OspE interface. These results suggest that the evolution of CFH and OspE may be shaped by broader selective pressures, potentially including interactions with multiple host species.

Social hierarchies are a nearly universal feature of animal groups, but whether dominance reflects a single generalized trait or a collection of context-specific competitive abilities remains unclear. Here, we assess social hierarchy in three strains of laboratory mice (BALB/c, C57BL/6, and Shank3B knockouts) of both sexes using three established paradigms: the tube test, the warm spot assay, and the void spot assay. Hierarchies emerged in all strains and both sexes across all three assays, but how animals established rank differed markedly by strain and sex. In the tube test, Shank3b-/- knockout females, but not males, lacked the winner effects seen in wild-type mice, indicating that the ability to build a winning streak depends on social recognition in a sex-specific manner. In the warm spot assay, females formed stronger hierarchies than males, particularly among mice on a C57BL/6 background, with high-ranking females actively displacing others from the warm platform. In the void spot assay, BALB/c mice of both sexes frequently displayed territory-marking behavior, a pattern that was less common in the other strains. Overall, individual rank rarely generalized across domains, despite high trial-to-trial repeatability for individuals within each assay. Together, these findings indicate that mice behave as dominance specialists rather than generalists, with strain- and sex-specific strategies for establishing rank in different competitive contexts, suggesting that distinct neural circuits likely underlie these separable components of competitive ability.

Observed group sizes rarely match the size that would maximize what each member gets from belonging. We propose a two-part theory in which group size is regulated by two related conflicts: insider-outsider conflict over admission, and within-group conflict as crowding, competition, and social tensions intensify with size. Three strategies are available: admission, exclusion, and fission. The first part shows that even when exclusion is unavailable, fission dynamics alone drive group size away from the optimum in both directions, with the pattern set by how prospective joiners encounter groups and by the geometry of fission. When joiners compare groups across a shared landscape and fission is asymmetric, the standing distribution is bimodal: supra-optimal large groups coexisting with a sub-optimal mode of small groups, the pattern characteristic of fission-fusion societies. The second part promotes exclusion and fission to active decisions: incumbents weigh the per-capita cost of accommodating entry ({beta}) against the costs of coordinated exclusion (c +{gamma} N*) and fissioning (F). A single inequality, {beta} > c +{gamma} N*, partitions populations into two regimes: where it holds, exclusion is viable and groups lock at the optimum size; where it fails, groups grow past the optimum and cycle through recurrent fission. Modal group size, fission frequency, and exclusion behavior together identify which regime governs a population -- a set of predictions applicable across fishes, social insects, birds, and mammals including primates and human foragers.

The rapid scale-up of HIV pre-exposure prophylaxis (PrEP) among men who have sex with men has coincided with rising rates of bacterial sexually transmitted infections (STIs), particularly Neisseria gonorrhoeae. This temporal association has raised concerns that PrEP may be driving a new STI epidemic. However, the epidemiological impact of PrEP reflects a trade-off between potential behavioral risk compensation, which increases transmission risk, and intensified clinical surveillance, which shortens infection duration. Determining whether PrEP amplifies or mitigates STI transmission therefore requires understanding how these competing effects balance at the population level. To address this question, we develop a transmission model stratified by sexual activity and PrEP use, derive simple analytical conditions governing changes in prevalence, incidence, and notification rates, and evaluate these dynamics using empirically informed parameter estimates. Our analysis demonstrates that current quarterly screening guidelines are generally sufficient to reduce both the true endemic prevalence and incidence of N. gonorrhoeae, successfully overcompensating for plausible reductions in condom use. We also confirm and expand on previous findings that clinical notification rates may surge even as the true disease burden declines, driven by the detection of previously undiagnosed asymptomatic infections. These findings suggest a shift in focus from the potential impact of PrEP on STI transmission to the consequences of increased STI diagnoses and treatment, particularly whether greater antibiotic consumption may accelerate the spread of antimicrobial resistance in N. gonorrhoeae.

Background Vaccination programs have greatly reduced the burden of infectious diseases, particularly in childhood. As populations age, however, the burden of respiratory infections such as influenza A, respiratory syncytial virus (RSV), and SARS-CoV-2 increasingly falls on older adults. Because infection fatality rates rise steeply with age, vaccination strategies that alter the age distribution of infections may have complex population-level consequences. We used transmission models to examine how the timing and frequency of vaccination influence infection-induced mortality and years of life lost (YLL) in aging populations. Methods and findings We analyzed age-structured transmission models that incorporate demographic change, age-specific infection fatality rates, and waning immunity after infection or vaccination. We varied the age at first vaccination, vaccination intervals, and coverage across a wide range of pathogen characteristics, including transmissibility and the duration of natural and vaccine-induced immunity. For single-dose vaccination programs with long-lived protection (5-50 years), the age at vaccination minimizing mortality in older adults for pathogens with strongly age-increasing fatality risk typically ranges from 60 to 80 years. The optimal age shifted toward older ages when transmissibility was higher or natural immunity lasted longer. Repeated vaccination produced qualitatively different outcomes. When vaccine-induced immunity was short-lived ($<$5 years), vaccination can shift infections toward the oldest ages where fatality risks are highest, increasing both mortality and YLL compared with no vaccination. This study has limitations. Our analysis used stylized transmission models and assumed vaccines that fully prevent infection, which may overestimate age-shifting effects compared with real-world vaccines that primarily reduce disease severity. Conclusions Optimal adult vaccination strategies depend jointly on pathogen transmissibility, the duration of immunity, and population demography. Vaccination programs that suppress infections earlier in life without protecting individuals into late life may shift infections toward ages with higher fatality risk. These findings highlight the need to evaluate adult vaccination strategies across the full life course and have important implications for vaccination policies against influenza A and other pathogens with strongly age-dependent infection fatality rates.

An epidemic's expected course is determined by the magnitude and timing of a typical person's infectiousness --- captured, in turn, by the basic reproduction number and the generation-time distribution. These fundamental, population-average quantities can mask individual-level variation that shapes how an epidemic actually unfolds: for example, individual variation in the magnitude of infectiousness (overdispersion) creates superspreading, a key feature of the SARS-CoV-1 and SARS-CoV-2 epidemics. However, the impact of individual variation in infectiousness timing is less well understood. Here, we demonstrate that individual infectiousness timing varies substantially and to different degrees across pathogens. For some common pathogens, including influenza, measles, and SARS-CoV-2, infectiousness is "bursty", or highly concentrated and variably-timed across individuals: for example, the window of appreciable infectiousness for SARS-CoV-2 may last for roughly a day, vs. the 9--12 days usually quoted. We show that bursty infectiousness creates superspreading without inherent superspreaders, makes epidemic timing more variable, amplifies the time-sensitivity of common interventions, and complicates inference of key epidemiological parameters. Together with the reproduction number, the generation-time distribution, and overdispersion, burstiness completes a family of basic parameters that govern how epidemics unfold.

Healthspan, the period of life where organisms are without frailty and/or disease, is a major focus of biogerontological research. To understand late-life decline and increased mortality risk, short-lived organisms such as nematode worms are commonly used. Pristionchus nematodes are established models for evolutionary developmental genetics research and show promise as systems for comparative and experimental study of ageing. To support this, we developed phenotypic ageing profiles for the evo-devo model Pristionchus pacificus and its little-studied congener Pristionchus fissidentatus. We find that various life history traits differ between P. pacificus and P. fissidentatus (lifespan, brood size, and reproductive period), demonstrating their utility for studying divergent ageing trajectories. Further, several traits are consistently impacted by age, including intestinal barrier function, body size, and locomotory ability. Additionally, in P. pacificus, rupture avoidance, cuticle integrity, and feeding rate decline with age, indicating dysregulation across many tissue types. Several age-linked patterns resemble those documented for Caenorhabditis elegans despite considerable evolutionary distance, suggesting conserved senescent processes across the Rhabditida family of nematodes. This work highlights similarities and differences in the impact of ageing in two Pristionchus nematodes and supports their development as models for evolutionary genetic study of senescence.

Many proposed mechanisms for the evolution of cooperation among unrelated individuals rely on relatively demanding cognitive abilities that are not widespread across taxa. In contrast, individual heterogeneity is a pervasive feature of animal groups, encompassing differences in personality as well as physical and cognitive traits. Such heterogeneity can promote the evolution of cooperation, yet its role has received comparatively little attention, particularly as a source of variation giving rise to social organization such as leadership. A specific form of leadership can emerge under unstable environmental conditions, when some individuals become better suited than others to initiate action and influence the behavior of their peers. Unlike fixed dominance hierarchies, emergent leadership can rapidly adjust to changing environmental conditions, thereby reshaping group organization. Because it does not require the maintenance of stable hierarchies, this form of leadership can arise even in species that do not have the cognitive capabilities to sustain complex social structures. In this work, we investigate the combined effects of individual heterogeneity and emergent leadership on the evolution of cooperation using an evolutionary game-theoretic model in which individuals may assume the roles of leaders or followers according to their strength, representing individual differences in suitability to prevailing environmental conditions. We examine different levels of population heterogeneity together with increasingly complex strategy sets requiring progressively greater informational requirements, allowing individuals to condition cooperation on their own strength, leadership role, or both. Our results show that the interplay between leadership and heterogeneity promotes the evolution of cooperation, particularly when only a small fraction of individuals act as leaders. Under these circumstances, cooperation evolves even when individuals employ the simplest possible strategies. Under harsher ecological conditions, cooperation can be sustained by more sophisticated strategies, specifically by conditional strategies that prescribe cooperation when individuals are strong or leading and defect when acting independently. Author summaryIn this study, we propose that emergent leadership mediated by individual diversity can boost the evolution of cooperation in animal groups. Building on growing evidence on the heterogeneity of animal capabilities and personalities, we focus on the fleeting leadership that emerges in animal groups when facing rapidly changing environmental conditions. We suggest that this type of leadership that emerges from individual differences in strength--a generic quality encompassing those characteristics that make an individual more fit to lead in a given situation--does not require complex cognitive capabilities from the animals and represents a valid alternative to more demanding strategies proposed in the past to explain the evolution of cooperation. Using an evolutionary game theory model, we show that if a population includes a few strong players, these can become influential leaders and guide the actions of their peers to achieve cooperation. Although the naive strategy of always cooperating is sufficient for cooperation to evolve, the introduction of more complex strategies leads players to cooperate only when they are more likely to be recognized as influential leaders. These strategies are more effective in promoting cooperation under unfavorable ecological conditions and are also more robust against exploitation by defectors.

Zika virus (ZIKV) is an arbovirus that usually causes few symptoms and has circulated endemically in Asia for decades. However, a large outbreak in South America in 2015 uncovered the serious risk of congenital Zika syndrome in infants born from ZIKV infected mothers. It is unknown whether a lineage with distinct pre-existing fitness advantage emerged from Asia to cause the South American outbreak, and whether there is ongoing evolution that can result in future globally fit strains. Here we used 107 sequences from a single setting (Thailand) collected over an 18 year period (2006-2023). We used novel analytical tools to identify distinct lineages that have circulated in the population and estimated their relative epidemiological fitness. We found there have been six lineages circulating sequentially in the country, with regular emergence and replacement of lineages showing higher fitness than their predecessors. We identified 15 lineage-defining amino acid changes, including four well-documented fitness-enhancing mutations, and two UTR substitutions. The lineage that emerged in South America was evolutionarily linked to the highest-fitness lineage in Thailand, carrying seven of our lineage-defining substitutions acquired during endemic circulation there, and subsequently accumulating four additional changes. After the global pandemic, endemic ZIKV in Thailand continued to evolve, with newly emerged lineages showing novel mutations and increased fitness. Our findings have key implications for the monitoring of ZIKV and can help identify the pathway to increased transmissibility of this globally important pathogen.

Antibiotics impose strong selection on bacteria, resulting in the emergence and spread of antimicrobial resistance. To date, the consequences of resistance evolution for other traits, especially virulence as a key life-history characteristic of high medical relevance remain poorly understood. A central limitation of existing work is reliance on clinical isolates with complex evolutionary histories, hindering causal inferences on resistance-virulence relationships. Such causal information is critical for our understanding of the distribution of resistance-associated evolutionary trade-offs, which may additionally guide optimization of treatment designs. The objectives of our study are to address these knowledge gaps using an experimental evolution framework with the human pathogen Pseudomonas aeruginosa. We quantified changes in resistance, life-history characteristics, in-vivo virulence with a Caenorhabditis elegans infection model, and whole genome sequences for bacterial clones, which had been independently evolved under three antibiotics with distinct cellular targets. We found that the resistance-virulence trade-off depended on the used antibiotic and was additionally driven by the underlying evolutionary path to resistance. Evolved resistance to the fluoroquinolone ciprofloxacin correlated positively with virulence, dependent on genetic changes in either the antibiotic target or efflux regulation. Conversely, evolved resistance to piperacillin/tazobactam, a {beta}-lactam/{beta}-lactamase inhibitor combination, was negatively correlated with virulence, contingent on the coincidental spread of resistance mutations and a large genomic deletion, containing numerous virulence genes. Lastly, evolved resistance to the aminoglycoside streptomycin led to only minor virulence changes. Overall, these antibiotic-specific evolutionary trajectories challenge the assumption of a universal resistance-virulence trade-off and demonstrate that antibiotic choice itself shapes pathogen virulence potential. Significance StatementAntimicrobial resistance and bacterial virulence are typically studied in isolation, yet they are shaped by the same evolutionary pressures and may directly compete for cellular resources. We addressed a fundamental but unresolved question: does evolution of resistance to an antibiotic make a pathogen more or less dangerous to a host? By characterizing experimentally evolved Pseudomonas aeruginosa, a leading cause of drug-resistant infections, we show that the answer depends on which antibiotic drove resistance. A positive resistance-virulence relationship occurred upon adaptation to a fluoroquinolone antibiotic, whereas it was negative upon {beta}-lactam resistance, and unchanged upon aminoglycoside resistance evolution. These antibiotic-specific evolutionary trajectories challenge the assumption of a universal resistance-virulence trade-off and suggest that antibiotic choice shapes pathogen danger beyond drug susceptibility.

Endothelial cells (ECs) express organ-specific gene programs supporting tissue homeostasis and resilience. However, the mechanisms by which aging reshapes these organ-specific endothelial programs and how the resulting changes affect tissue homeostasis, resilience, and disease susceptibility remain largely unknown. Herein, we performed single-cell RNA sequencing of ECs harvested from five organs across the lifespan and found that aging progressively erodes organ-specific endothelial programs while inducing shared interferon-responsive and antigen-presentation programs across organs. Although vascular subtype identity and conserved capillary subset identity were mostly preserved, these organ-specific transcriptional programs were broadly attenuated with aging, indicating erosion of organ-specific endothelial identity to be a fundamental feature of endothelial aging. Importantly, these alterations were associated with declines in specialized EC functions, including alveolar barrier maintenance in the lung, scavenging activity in the liver, angiogenic capacity in the heart, and homeostatic programs in the kidneys and the brain, suggesting that age-related EC alterations compromise tissue homeostasis and resilience in multiple organs. Furthermore, we established a single-cell aging index for alveolar capillary ECs in mice and humans, revealing stress-associated endothelial activation to potentially be an intermediate state linking functional deterioration to cellular senescence, and also demonstrating marked heterogeneity in aging states among ECs of the same chronological age. Notably, alveolar capillary ECs exhibited progressive functional decline before reaching a senescent-like state, suggesting endothelial dysfunction to precede overt cellular senescence as the organism ages. Collectively, our findings establish progressive erosion of organ-specific endothelial programs as a central feature of vascular aging and provide a conceptual framework for elucidating how endothelial aging contributes to tissue dysfunction and reduced resilience across organs.

Germinal centers (GCs) support physiological B-cell mutagenesis and are considered lymphoma-permissive; nevertheless, lymphoma development is uncommon. Human in situ follicular neoplasia (ISFN) captures this paradox: premalignant B-cells can persist within GCs for prolonged periods without progressing to overt lymphoma. We found that human ISFN, but not normal GCs, are infiltrated by CD8 T-cells, suggesting that premalignant GC B-cells are locally immune-surveilled. Using mouse models that separate early premalignant fitness from lymphoma-associated evolution, we show that fitness-enhanced premalignant GC B-cells expand transiently but are selectively eliminated by infiltrating cytotoxic CD8 T-cells, while normal GC B-cells are spared. By contrast, evolved premalignant GC B-cells retain their fitness but disable productive CD8 T-cell cytotoxic differentiation, allowing persistence and lymphoma-like transcriptional and genomic evolution. These findings establish GCs as active immune-surveillance sites and show that progression from premalignancy to lymphoma requires both enhanced GC fitness and escape from local immune control. Key findingsGCs undergo active immune-surveillance to detect premalignant B-cells. Premalignant GC B-cells trigger cytotoxic CD8 T-cell responses. Lymphoma-associated evolution enables immune-escape within GCs. Fitness and immune-escape drive evolution from premalignancy to lymphoma. BlurbGerminal centers are considered lymphoma-permissive; however, progression from premalignancy is uncommon. Using models of human in situ follicular neoplasia, Zhang et al. demonstrate that infiltrating CD8 T-cells actively eliminate premalignant GC B-cells. Co-occurrence of lymphoma-like alterations blocks this cytotoxic T-cell response, driving immune escape and lymphoma evolution.