Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy.

CD4+ T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses1-5, other CD4+ T cells have recently been implicated in inhibiting this response6,7. Yet, the nature and function of the latter remain unclear. Here, using vaccines containing MHC class I (MHC-I) neoantigens (neoAgs) and different doses of tumour-derived MHC-II neoAgs, we discovered that whereas the inclusion of vaccines with low doses of MHC-II-restricted peptides (LDVax) promoted tumour rejection, vaccines containing high doses of the same MHC-II neoAgs (HDVax) inhibited rejection. Characterization of the inhibitory cells induced by HDVax identified them as type 1 regulatory T (Tr1) cells expressing IL-10, granzyme B, perforin, CCL5 and LILRB4. Tumour-specific Tr1 cells suppressed tumour rejection induced by anti-PD1, LDVax or adoptively transferred tumour-specific effector T cells. Mechanistically, HDVax-induced Tr1 cells selectively killed MHC-II tumour antigen-presenting type 1 conventional dendritic cells (cDC1s), leading to low numbers of cDC1s in tumours. We then documented modalities to overcome this inhibition, specifically via anti-LILRB4 blockade, using a CD8-directed IL-2 mutein, or targeted loss of cDC2/monocytes. Collectively, these data show that cytotoxic Tr1 cells, which maintain peripheral tolerance, also inhibit antitumour responses and thereby function to impede immune control of cancer.

Publisher Correction: Cryptic connections illuminate pathogen transmission within community networks.

In Fig. 3d this Letter, the R2 value should have been '0.19' instead of '0.66'; this has been corrected online.

MHC-II neoantigens shape tumour immunity and response to immunotherapy.

The ability of the immune system to eliminate and shape the immunogenicity of tumours defines the process of cancer immunoediting1. Immunotherapies such as those that target immune checkpoint molecules can be used to augment immune-mediated elimination of tumours and have resulted in durable responses in patients with cancer that did not respond to previous treatments. However, only a subset of patients benefit from immunotherapy and more knowledge about what is required for successful treatment is needed2-4. Although the role of tumour neoantigen-specific CD8+ T cells in tumour rejection is well established5-9, the roles of other subsets of T cells have received less attention. Here we show that spontaneous and immunotherapy-induced anti-tumour responses require the activity of both tumour-antigen-specific CD8+ and CD4+ T cells, even in tumours that do not express major histocompatibility complex (MHC) class II molecules. In addition, the expression of MHC class II-restricted antigens by tumour cells is required at the site of successful rejection, indicating that activation of CD4+ T cells must also occur in the tumour microenvironment. These findings suggest that MHC class II-restricted neoantigens have a key function in the anti-tumour response that is nonoverlapping with that of MHC class I-restricted neoantigens and therefore needs to be considered when identifying patients who will most benefit from immunotherapy.

Southern Hemisphere climate variability forced by Northern Hemisphere ice-sheet topography.

The presence of large Northern Hemisphere ice sheets and reduced greenhouse gas concentrations during the Last Glacial Maximum fundamentally altered global ocean-atmosphere climate dynamics. Model simulations and palaeoclimate records suggest that glacial boundary conditions affected the El Niño-Southern Oscillation, a dominant source of short-term global climate variability. Yet little is known about changes in short-term climate variability at mid- to high latitudes. Here we use a high-resolution water isotope record from West Antarctica to demonstrate that interannual to decadal climate variability at high southern latitudes was almost twice as large at the Last Glacial Maximum as during the ensuing Holocene epoch (the past 11,700 years). Climate model simulations indicate that this increased variability reflects an increase in the teleconnection strength between the tropical Pacific and West Antarctica, owing to a shift in the mean location of tropical convection. This shift, in turn, can be attributed to the influence of topography and albedo of the North American ice sheets on atmospheric circulation. As the planet deglaciated, the largest and most abrupt decline in teleconnection strength occurred between approximately 16,000 years and 15,000 years ago, followed by a slower decline into the early Holocene.

Publisher Correction: Magnetoelectric inversion of domain patterns.

Four incorrect figure citations in this Letter have been corrected online.

Magnetoelectric inversion of domain patterns.

The inversion of inhomogeneous physical states has great technological importance; for example, active noise reduction relies on the emission of an inverted sound wave that interferes destructively with the noise of the emitter1, and inverting the evolution of a spin system by using a magnetic-field pulse enables magnetic resonance tomography2. In contrast to these examples, inversion of a distribution of ferromagnetic or ferroelectric domains within a material is surprisingly difficult: field poling creates a single-domain state, and piece-by-piece inversion using a scanning tip is impractical. Here we report inversion of entire ferromagnetic and ferroelectric domain patterns in the magnetoelectric material Co3TeO6 and the multiferroic material Mn2GeO4, respectively. In these materials, an applied magnetic field reverses the magnetization or polarization, respectively, of each domain, but leaves the domain pattern intact. Landau theory indicates that this type of magnetoelectric inversion is universal across materials that exhibit complex ordering, with one order parameter holding the memory of the domain structure and another setting its overall sign. Domain-pattern inversion is only one example of a previously unnoticed effect in systems such as multiferroics, in which several order parameters are available for combination. Exploring these effects could therefore advance multiferroics towards new levels of functionality.

Cryptic connections illuminate pathogen transmission within community networks.

Understanding host interactions that lead to pathogen transmission is fundamental to the prediction and control of epidemics1-5. Although the majority of transmissions often occurs within social groups6-9, the contribution of connections that bridge groups and species to pathogen dynamics is poorly understood10-12. These cryptic connections-which are often indirect or infrequent-provide transmission routes between otherwise disconnected individuals and may have a key role in large-scale outbreaks that span multiple populations or species. Here we quantify the importance of cryptic connections in disease dynamics by simultaneously characterizing social networks and tracing transmission dynamics of surrogate-pathogen epidemics through eight communities of bats. We then compared these data to the invasion of the fungal pathogen that causes white-nose syndrome, a recently emerged disease that is devastating North American bat populations13-15. We found that cryptic connections increased links between individuals and between species by an order of magnitude. Individuals were connected, on average, to less than two per cent of the population through direct contact and to only six per cent through shared groups. However, tracing surrogate-pathogen dynamics showed that each individual was connected to nearly fifteen per cent of the population, and revealed widespread transmission between solitarily roosting individuals as well as extensive contacts among species. Connections estimated from surrogate-pathogen epidemics, which include cryptic connections, explained three times as much variation in the transmission of the fungus that causes white-nose syndrome as did connections based on shared groups. These findings show how cryptic connections facilitate the community-wide spread of pathogens and can lead to explosive epidemics.

Radiation-induced neoantigens broaden the immunotherapeutic window of cancers with low mutational loads.

Immunotherapies are a promising advance in cancer treatment. However, because only a subset of cancer patients benefits from these treatments it is important to find mechanisms that will broaden the responding patient population. Generally, tumors with high mutational burdens have the potential to express greater numbers of mutant neoantigens. As neoantigens can be targets of protective adaptive immunity, highly mutated tumors are more responsive to immunotherapy. Given that external beam radiation 1) is a standard-of-care cancer therapy, 2) induces expression of mutant proteins and potentially mutant neoantigens in treated cells, and 3) has been shown to synergize clinically with immune checkpoint therapy (ICT), we hypothesized that at least one mechanism of this synergy was the generation of de novo mutant neoantigen targets in irradiated cells. Herein, we use KrasG12D x p53-/- sarcoma cell lines (KP sarcomas) that we and others have shown to be nearly devoid of mutations, are poorly antigenic, are not controlled by ICT, and do not induce a protective antitumor memory response. However, following one in vitro dose of 4- or 9-Gy irradiation, KP sarcoma cells acquire mutational neoantigens and become sensitive to ICT in vivo in a T cell-dependent manner. We further demonstrate that some of the radiation-induced mutations generate cytotoxic CD8+ T cell responses, are protective in a vaccine model, and are sufficient to make the parental KP sarcoma line susceptible to ICT. These results provide a proof of concept that induction of new antigenic targets in irradiated tumor cells represents an additional mechanism explaining the clinical findings of the synergy between radiation and immunotherapy.

Sex-biased infections scale to population impacts for an emerging wildlife disease.

Demographic factors are fundamental in shaping infectious disease dynamics. Aspects of populations that create structure, like age and sex, can affect patterns of transmission, infection intensity and population outcomes. However, studies rarely link these processes from individual to population-scale effects. Moreover, the mechanisms underlying demographic differences in disease are frequently unclear. Here, we explore sex-biased infections for a multi-host fungal disease of bats, white-nose syndrome, and link disease-associated mortality between sexes, the distortion of sex ratios and the potential mechanisms underlying sex differences in infection. We collected data on host traits, infection intensity and survival of five bat species at 42 sites across seven years. We found females were more infected than males for all five species. Females also had lower apparent survival over winter and accounted for a smaller proportion of populations over time. Notably, female-biased infections were evident by early hibernation and likely driven by sex-based differences in autumn mating behaviour. Male bats were more active during autumn which likely reduced replication of the cool-growing fungus. Higher disease impacts in female bats may have cascading effects on bat populations beyond the hibernation season by limiting recruitment and increasing the risk of Allee effects.

Widespread Community Transmission of Hepatitis A Virus Following an Outbreak at a Local Restaurant - Virginia, September 2021-September 2022.

Hepatitis A is a vaccine-preventable liver infection caused by the hepatitis A virus (HAV); it is transmitted through ingestion of food or drink that has been contaminated by small amounts of infected stool, or through direct contact, including sexual contact, with a person who is infected (1). After years of historically low rates of hepatitis A in the United States, the incidence began increasing in 2016, with outbreaks characterized by person-to-person HAV transmission among persons who use drugs, persons experiencing homelessness, and men who have sex with men (2,3). As of September 2022, 13 states were experiencing outbreaks, including Virginia (3). In September 2021, the Roanoke City and Alleghany Health Districts (RCAHD) in southwestern Virginia investigated an outbreak of hepatitis A. The outbreak, which resulted in 51 cases, 31 hospitalizations, and three deaths, was associated with a food handler who was infected. After the outbreak, the community experienced ongoing person-to-person transmission of HAV, predominantly among persons who use injection drugs. As of September 30, 2022,* an additional 98 cases had been reported to RCAHD. The initial outbreak and community transmission have exceeded US$3 million in estimated direct costs (4,5). This report describes the initial outbreak and the ongoing community transmission of HAV. Increasing vaccination coverage among persons with risk factors for hepatitis A infection is important, including among those who use drugs. Strengthening community partnerships between public health officials and organizations that employ persons with risk factors for acquisition of HAV could help to prevent infections and outbreaks.

Shifting effects of host physiological condition following pathogen establishment.

Understanding host persistence with emerging pathogens is essential for conserving populations. Hosts may initially survive pathogen invasions through pre-adaptive mechanisms. However, whether pre-adaptive traits are directionally selected to increase in frequency depends on the heritability and environmental dependence of the trait and the costs of trait maintenance. Body condition is likely an important pre-adaptive mechanism aiding in host survival, although can be seasonally variable in wildlife hosts. We used data collected over 7 years on bat body mass, infection and survival to determine the role of host body condition during the invasion and establishment of the emerging disease, white-nose syndrome. We found that when the pathogen first invaded, bats with higher body mass were more likely to survive, but this effect dissipated following the initial epizootic. We also found that heavier bats lost more weight overwinter, but fat loss depended on infection severity. Lastly, we found mixed support that bat mass increased in the population after pathogen arrival; high annual plasticity in individual bat masses may have reduced the potential for directional selection. Overall, our results suggest that some factors that contribute to host survival during pathogen invasion may diminish over time and are potentially replaced by other host adaptations.

Environmental reservoir dynamics predict global infection patterns and population impacts for the fungal disease white-nose syndrome.

Disease outbreaks and pathogen introductions can have significant effects on host populations, and the ability of pathogens to persist in the environment can exacerbate disease impacts by fueling sustained transmission, seasonal epidemics, and repeated spillover events. While theory suggests that the presence of an environmental reservoir increases the risk of host declines and threat of extinction, the influence of reservoir dynamics on transmission and population impacts remains poorly described. Here we show that the extent of the environmental reservoir explains broad patterns of host infection and the severity of disease impacts of a virulent pathogen. We examined reservoir and host infection dynamics and the resulting impacts of Pseudogymnoascus destructans, the fungal pathogen that causes white-nose syndrome, in 39 species of bats at 101 sites across the globe. Lower levels of pathogen in the environment consistently corresponded to delayed infection of hosts, fewer and less severe infections, and reduced population impacts. In contrast, an extensive and persistent environmental reservoir led to early and widespread infections and severe population declines. These results suggest that continental differences in the persistence or decay of P. destructans in the environment altered infection patterns in bats and influenced whether host populations were stable or experienced severe declines from this disease. Quantifying the impact of the environmental reservoir on disease dynamics can provide specific targets for reducing pathogen levels in the environment to prevent or control future epidemics.

Highly reliable creation of floxed alleles by electroporating single-cell embryos.

BACKGROUND: Floxed (flanked by loxP) alleles are a crucial portion of conditional knockout mouse models. However, an efficient and reliable strategy to flox genomic regions of any desired size is still lacking. RESULTS: Here, we demonstrate that the method combining electroporation of fertilized eggs with gRNA/Cas9 complexes and single-stranded oligodeoxynucleotides (ssODNs), assessing phasing of loxP insertions in founders using an in vitro Cre assay and an optional, highly specific and efficient second-round targeting ensures the generation of floxed F1 animals in roughly five months for a wide range of sequence lengths (448 bp to 160 kb reported here). CONCLUSIONS: Floxed alleles can be reliably obtained in a predictable timeline using the improved method of electroporation of two gRNA/Cas9 ribonucleoprotein particles (RNPs) and two ssODNs.

Field applications of zein as a precise nanoscale delivery system for methoxyfenozide.

When insecticides are applied in the environment, much of the product does not reach the target pest. Biopolymeric nanoparticles as nanocarriers have the potential to improve insecticide efficacy by improving absorption, coverage, and permeability while protecting the insecticide active ingredient from abiotic conditions and extending efficacy through controlled release. We conducted a series of experiments using a biopolymeric nanoparticle synthesized from zein, a biodegradable maize protein, to compare efficacy of a nanodelivered hydrophobic insect growth regulator (methoxyfenozide) against a commercial formulation. Positively charged zein nanoparticles (empty and loaded with methoxyfenozide) were compared to the formulated product, Intrepid 2F, as a foliar spray in-field on soybean. Chrysodeixis includens (Walker) was used as a model and was fed sprayed soybean leaves to evaluate efficacy of the tested foliar products over time. A separate set of leaves was sampled to measure residue levels of methoxyfenozide (MFZ) over time following foliar application using QuEChERS extraction and high-resolution liquid chromatography-mass spectrometry. Regression analysis found no differences in mortality slopes between positively charged zein nanoparticles loaded with methoxyfenozide [(+)ZNP(MFZ)] and Intrepid 2F, suggesting comparable efficacy of the synthesized nanoparticles to a commercial product. Higher concentrations of MFZ were present in (+)ZNP(MFZ)-treated in leaf tissue at 3 d following spray when compared to Intrepid 2F. The multiyear study results demonstrate that nanoparticles loaded with MFZ are comparable to Intrepid 2F under field conditions, with potential short-term benefits.

The impacts of adrenoleukodystrophy newborn screening on the evaluation of adrenal dysfunction in male children: An integrative literature review.

PROBLEM: Adrenoleukodystrophy (ALD) is an x-linked genetic condition with a high risk of adrenal dysfunction recommended for newborn screening. This review aims to critically appraise and synthesize existing literature identifying the impacts of ALD newborn screening in the United States on the evaluation and treatment of adrenal dysfunction in male children. ELIGIBILITYCRITERIA: An integrative literature review was conducted using the Embase, PubMed, and CINAHL databases. English-language primary source studies published in the past decade and seminal studies were included. SAMPLE: Twenty primary sources met the inclusion criteria, including five seminal studies. RESULTS: Three major themes emerged from the review: 1) prevention of adrenal crisis, 2) unexpected outcomes, and 3) ethical impacts. CONCLUSIONS: ALD screening increases disease identification. Serial adrenal evaluation prevents adrenal crisis and death; data is needed to establish predictive outcomes in ALD prognosis. Disease incidence and prognosis will become more apparent as states increasingly add ALD screening to their newborn panel. IMPLICATIONS FOR PRACTICE: Clinicians need awareness of ALD newborn screening and state screening protocols. Families first learning of ALD through newborn screening results will require education, support, and timely referrals for appropriate care.

Rupture of the gastrocnemius muscle at its distal musculotendinous junction: conservative treatment and outcomes in 11 dogs.

CASE HISTORY: Medical records from three veterinary referral centres and a university veterinary teaching hospital in Australia and the USA were reviewed to identify dogs with a diagnosis of distal gastrocnemius musculotendinous junction rupture (DGMJR) that were treated without surgery between 2007 and 2020. CLINICAL AND IMAGING FINDINGS: All dogs (n = 11) presented with unilateral, pelvic limb lameness and bruising, swelling or pain on palpation at the distal musculotendinous junction. The diagnosis was confirmed with ultrasound or MRI in six dogs; radiographs were used to excluded stifle and tarsus pathology in four dogs; and five dogs were diagnosed on physical examination findings. TREATMENT AND OUTCOME: All dogs were managed conservatively, either with complete confinement alone (n = 10; median 9 weeks), external coaptation alone (n = 1), or a combination of both (n = 4). Sporting dogs (n = 7) were completely confined (median 22 weeks) for longer periods than companion dogs (n = 3; median 5 weeks).A good to excellent outcome was achieved for all cases in this cohort. The seven sporting dogs achieved an excellent outcome; returning to their previous level of sport, with complete resolution of lameness and recovery of a normal tibiotarsal stance. The four companion dogs achieved a good outcome; returning to their previous level of activity but with persistently increased tibiotarsal standing angle compared to the contralateral limb. CLINICAL RELEVANCE: Conservative treatment represents a viable treatment option for dogs with a rupture of the gastrocnemius muscle at its distal musculotendinous junction.

No-take marine protected areas enhance the benefits of kelp-forest restoration for fish but not fisheries.

Kelp habitat restoration is gaining traction as a management action to support recovery in areas affected by severe disturbances, thereby ensuring the sustainability of ecosystem services. Knowing when and where to restore is a major question. Using a single-species population model, we consider how restoring inside marine protected areas (MPAs) might benefit coastal fish populations and fisheries. We found that MPAs can greatly enhance the population benefits of restoration but at a small cost to fishery yields. Generally, restoring inside MPAs had a better overall gains-loss outcome, especially if the system is under high fishing pressure or severe habitat loss. However, restoring outside became preferable when predatory fish indirectly benefit kelp habitats. In either case, successful restoration actions may be difficult to detect in time-series data due to complex transient dynamics. We provide context for setting management goals and social expectations for the ecosystem service implications of restoration in MPAs.

HLA class II immunogenic mutation burden predicts response to immune checkpoint blockade.

BACKGROUND: Whereas human leukocyte antigen (HLA) class I mutation-associated neoantigen burden has been linked with response to immune checkpoint blockade (ICB), the role of HLA class II-restricted neoantigens in clinical responses to ICB is less studied. We used computational approaches to assess HLA class II immunogenic mutation (IMM) burden in patients with melanoma and lung cancer treated with ICB. PATIENTS AND METHODS: We analyzed whole-exome sequence data from four cohorts of ICB-treated patients with melanoma (n = 110) and non-small-cell lung cancer (NSCLC) (n = 123). MHCnuggets, a neural network-based model, was applied to estimate HLA class II IMM burdens and cellular fractions of IMMs were calculated to assess mutation clonality. We evaluated the combined impact of HLA class II germline genetic variation and class II IMM burden on clinical outcomes. Correlations between HLA class II IMM burden and density of tumor-infiltrating lymphocytes were computed from expression data. RESULTS: Responding tumors harbored a significantly higher HLA class II IMM burden for both melanoma and NSCLC (P ≤ 9.6e-3). HLA class II IMM burden was correlated with longer survival, particularly in the NSCLC cohort and in the context of low intratumoral IMM heterogeneity (P < 0.001). HLA class I and II IMM landscapes were largely distinct suggesting a complementary role for class II IMMs in tumor rejection. A higher HLA class II IMM burden was associated with CD4+ T-cell infiltration and programmed death-ligand 1 expression. Transcriptomic analyses revealed an inflamed tumor microenvironment for tumors harboring a high HLA class II IMM burden. CONCLUSIONS: HLA class II IMM burden identified patients with NSCLC and melanoma that attained longer survival after ICB treatment. Our findings suggest that HLA class II IMMs may impact responses to ICB in a manner that is distinct and complementary to HLA class I-mediated responses.

Recruitment variability and sampling design interact to influence the detectability of protected area effects.

Correctly identifying the effects of a human impact on a system is a persistent challenge in ecology, driven partly by the variable nature of natural systems. This is particularly true in many marine fishery species, which frequently experience large temporal fluctuations in recruitment that produce interannual variations in populations. This variability complicates efforts to maintain stocks at management targets or detect the effects of rebuilding efforts. We address this challenge in the context of no-take marine reserves by exploring how variable larval recruitment could interact with the timing of reserve establishment and choice of sampling design to affect population dynamics and the detectability of reserve effects. To predict population changes in the years following a no-take reserve implementation, we first tested for periodicity in larval recruitment in an important U.S. Pacific coast recreational fishery species (kelp bass, Paralabrax clathratus) and then included that pattern in a population model. We also used this model to determine the detectability of population increases under alternative sampling approaches and minimum age sampled. Kelp bass larval recruitment in the Channel Islands, California, peaked every about six (major) and about two (minor) years. Our model showed that establishing a reserve during a peak or trough enhanced or delayed, respectively, the post-reserve population increases. However, establishing a reserve during a recruitment peak could obscure a failing reserve, that is, a reserve that is unable to secure longer-term metapopulation persistence. Recruitment peaks and troughs also interacted with sampling design to affect the detectability of reserve effects. Designs that compared inside-outside were the most robust to variable recruitment, but failed to capture whether the reserve has improved metapopulation growth. Designs that included a time element (e.g., before-after) are more suited to assessing reserve effectiveness, but were sensitive to recruitment variation and detectability can change year-to-year. Notably, detectability did not always increase monotonically with reserve age; the optimal time for detectability depended on the minimum age of organisms sampled and was greatest when the cohort of a major recruitment peak first appeared in the sampling. We encourage managers to account for variable recruitment when planning monitoring and assessment programs.

Pulse disturbances in age-structured populations: Life history predicts initial impact and recovery time.

Understanding population responses to discrete 'pulsed' environmental disturbances is essential to conservation and adaptive management. Populations of concern can be driven to low levels by disturbance, and understanding interspecific differences in recovery trajectories is necessary for evaluating management options. We analysed single-species models to investigate the demographic and management factors determining the two components of population 'resilience': the magnitude of initial impact on population abundance, and duration of the recovery time. We simulated age-structured populations with density-dependent recruitment, subjected to a pulse disturbance consisting of a period of increased mortality of either the juvenile age class or all age classes, and calculated both impact and return time. For illustration, we used demographic parameters from a suite of 16 fish species. We formulated the model as a renewal equation, allowing us to describe disturbance impacts mathematically as a convolution. We also included nonlinear dynamics, representing populations that recover to a steady state; this is more realistic (in most cases) than prior analyses of resilience in linear models without density-dependence. When the disturbance affected only one or a few young age-classes, longevity was the major life-history determinant of impact and recovery time. Shorter-lived species endured greater impacts when disturbed because each age class is a greater proportion of the population. However, shorter-lived species also had faster recovery times, for the same reason. When disturbance affected adult age-classes, the impact was more immediate and no longer affected by species' longevity, though the effect of longevity on recovery time remained. These results improve our understanding of interspecific differences in resilience and increase our ability to make predictions for adaptive management. Additionally, formulating the problem as a renewal equation and using mathematical convolutions allows us to quantify how disturbances with different time courses (not just an immediate, constant level of disturbance but gradually increasing or decreasing levels of disturbance) would have different effects on population resilience: delayed responses for species in which biomass is concentrated in older age classes, and for disturbances that become progressively more severe.

Entender las respuestas de la población a perturbaciones ambientales, específicamente a pulsadas individuales, es esencial para la conservación y la gestión adaptativa. Las poblaciones de interés pueden reducirse a niveles bajas debido a la perturbación, y es necesario entender las diferencias interespecíficas en las trayectorias de recuperación para evaluar las opciones de gestión. Analizamos modelos para especies individuales para investigar los factores demográficos y de gestión que determinan los dos componentes de la 'resiliencia' de la población: la magnitud del impacto inicial sobre la abundancia de la población y la duración del tiempo de recuperación. Simulamos poblaciones estructuradas por edad con reclutamiento que depende de la densidad, las sometimos a una perturbación pulsada que consiste en un período de mayor mortalidad del grupo etário juvenil o de todos los grupos etários, y calculamos tanto el impacto como el tiempo de retorno. A modo de ilustración, utilizamos parámetros demográficos de un conjunto de 16 especies de peces. Formulamos el modelo como una ecuación de renovación, lo que nos permite describir matemáticamente los impactos de las perturbaciones como una convolución. También incluimos dinámicas no lineales que representan poblaciones que se recuperan hacia un estado estable; esto es más realista (en la mayoría de los casos) que los análisis previos de resiliencia en modelos lineales sin la dependencia de la densidad. Cuando la perturbación ha afectado a uno o a algunos pocos grupos etários jóvenes, la longevidad fue el principal determinante de la historia de vida del impacto y el tiempo de recuperación. Las especies de vida más corta sufrieron mayores impactos cuando fueron perturbadas porque cada grupo etáreo representa una mayor proporción de la población. Sin embargo, las especies con vidas más cortas también tuvieron tiempos de recuperación más rápidos, por la misma razón. Cuando la perturbación afectó a los grupos etários adultos, el impacto fue más inmediato y ya no se vio afectado por la longevidad de las especies, aunque se mantuvo el efecto de la longevidad sobre el tiempo de recuperación. Estos resultados mejoran nuestra comprensión de las diferencias interespecíficas de la resiliencia y aumentan nuestra capacidad para hacer predicciones con fin a la gestión adaptativa. Además, formular el problema como una ecuación de renovación y usar convoluciones matemáticas nos permite cuantificar cómo las perturbaciones con distintos lapsos de tiempo (no solo un nivel de perturbación constante e inmediato, sino niveles de perturbación que aumentan o disminuyen gradualmente) tendrían diferentes efectos sobre la resiliencia de la población: respuestas tardías para especies en las que la biomasa se concentra en grupos etários de mayor edad y para perturbaciones que se vuelven progresivamente más severas.