Sex ratio distorting microbes exacerbate arthropod extinction risk in variable environments.

Maternally-inherited sex ratio distorting microbes (SRDMs) are common among arthropod species. Typically, these microbes cause female-biased sex ratios in host broods, either by; killing male offspring, feminising male offspring, or inducing parthenogenesis. As a result, infected populations can experience drastic ecological and evolutionary change. The mechanism by which SRDMs operate is likely to alter their impact on host evolutionary ecology; despite this, the current literature is heavily biased towards a single mechanism of sex ratio distortion, male-killing. Furthermore, amidst the growing concerns surrounding the loss of arthropod diversity, research into the impact of SRDMs on the viability of arthropod populations is generally lacking. In this study, using a theoretical approach, we model the epidemiology of an understudied mechanism of microbially-induced sex ratio distortion-feminisation-to ask an understudied question-how do SRDMs impact extinction risk in a changing environment? We constructed an individual-based model and measured host population extinction risk under various environmental and epidemiological scenarios. We also used our model to identify the precise mechanism modulating extinction. We find that the presence of feminisers increases host population extinction risk, an effect that is exacerbated in highly variable environments. We also identified transmission rate as the dominant epidemiological trait responsible for driving extinction. Finally, our model shows that sex ratio skew is the mechanism driving extinction. We highlight feminisers and, more broadly, SRDMs as important determinants of the resilience of arthropod populations to environmental change.

A theoretical model for host-controlled regulation of symbiont density.

There is growing empirical evidence that animal hosts actively control the density of their mutualistic symbionts according to their requirements. Such active regulation can be facilitated by compartmentalization of symbionts within host tissues, which confers a high degree of control of the symbiosis to the host. Here, we build a general theoretical framework to predict the underlying ecological drivers and evolutionary consequences of host-controlled endosymbiont density regulation for a mutually obligate association between a host and a compartmentalized, vertically transmitted symbiont. Building on the assumption that the costs and benefits of hosting a symbiont population increase with symbiont density, we use state-dependent dynamic programming to determine an optimal strategy for the host, i.e., that which maximizes host fitness, when regulating the density of symbionts. Simulations of active host-controlled regulation governed by the optimal strategy predict that the density of the symbiont should converge to a constant level during host development, and following perturbation. However, a similar trend also emerges from alternative strategies of symbiont regulation. The strategy which maximizes host fitness also promotes symbiont fitness compared to alternative strategies, suggesting that active host-controlled regulation of symbiont density could be adaptive for the symbiont as well as the host. Adaptation of the framework allowed the dynamics of symbiont density to be predicted for other host-symbiont ecologies, such as for non-essential symbionts, demonstrating the versatility of this modelling approach.

Mechanistic modelling of within-mosquito viral dynamics: Insights into infection and dissemination patterns.

Vector or host competence can be defined as the ability of an individual to become infected and subsequently transmit a pathogen. Assays to measure competence play a key part in the assessment of the factors affecting mosquito-borne virus transmission and of potential pathogen-blocking control tools for these viruses. For mosquitoes, competence for arboviruses can be measured experimentally and results are usually analysed using standard statistical approaches. Here we develop a mechanistic approach to studying within-mosquito virus dynamics that occur during vector competence experiments. We begin by developing a deterministic model of virus replication in the mosquito midgut and subsequent escape and replication in the hemocoel. We then extend this to a stochastic model to capture the between-individual variation observed in vector competence experiments. We show that the dose-response of the probability of mosquito midgut infection and variation in the dissemination rate can be explained by stochastic processes generated from a small founding population of virions, caused by a relatively low rate of virion infection of susceptible cells. We also show that comparing treatments or species in competence experiments by fitting mechanistic models could provide further insight into potential differences. Generally, our work adds to the growing body of literature emphasizing the importance of intrinsic stochasticity in biological systems.

Inclusive fitness forces of selection in an age-structured population.

Hamilton's force of selection acting against age-specific mortality is constant and maximal prior to the age of first reproduction, before declining to zero at the age of last reproduction. The force of selection acting on age-specific reproduction declines monotonically from birth in a growing or stationary population. Central to these results is the assumption that individuals do not interact with one another. This assumption is violated in social organisms, where an individual's survival and/or reproduction may shape the inclusive fitness of other group members. Yet, it remains unclear how the forces of selection might be modified when inclusive fitness, rather than population growth rate, is considered the appropriate metric for fitness. Here, we derive such inclusive fitness forces of selection, and show that selection on age-specific survival is not always constant before maturity, and can remain above zero in post-reproductive age classes. We also show how the force of selection on age-specific reproduction does not always decline monotonically from birth, but instead depends on the balance of costs and benefits of increasing reproduction to both direct and indirect fitness. Our theoretical framework provides an opportunity to expand our understanding of senescence across social species.

Reducing intrusive memories after trauma via an imagery-competing task intervention in COVID-19 intensive care staff: a randomised controlled trial.

Intrusive memories (IMs) after traumatic events can be distressing and disrupt mental health and functioning. We evaluated the impact of a brief remotely-delivered digital imagery-competing task intervention on the number of IMs for intensive care unit (ICU) staff who faced repeated trauma exposure during the COVID-19 pandemic using a two-arm, parallel-group, single-blind randomised controlled trial, with the comparator arm receiving delayed access to active treatment (crossover). Eligible participants worked clinically in a UK NHS ICU during the pandemic and had at least 3 IMs of work-related traumatic events in the week before recruitment. Participants were randomly assigned (1:1) to immediate (weeks 1-4) or delayed (weeks 5-8) intervention access. Sequential Bayesian analyses to optimise the intervention and increase trial efficiency are reported elsewhere [1]. The primary endpoint for the pre-specified frequentist analysis of the final study population compared the number of IMs experienced in week 4 between the immediate and delayed access arms. Secondary outcomes included clinical symptoms, work functioning and wellbeing. Safety was assessed throughout the trial by scheduled questions and free report. All analyses were undertaken on an intention-to-treat basis (86 randomised participants). There were significantly fewer intrusive memories during week 4 in the immediate (median = 1, IQR = 0-3, n = 43), compared to the comparator delayed arm (median = 10, IQR = 6-17, n = 43), IRR 0.31, 95% CI: 0.20-0.48, p < 0.001. After crossover, the delayed arm also showed a significant reduction in IMs at week 8 compared to week 4. There were convergent findings for symptoms of PTSD, insomnia and anxiety, work engagement and burnout, general functioning and quality of life. The intervention was found safe and acceptable to participants. All adverse events were unrelated to the study. Our study provides the first evidence of a benefit on reducing IMs, improving other clinical symptoms, work functioning and wellbeing, as well as safety of a brief remotely-delivered digital imagery-competing task intervention. An efficacy trial with an active control and longer follow-up is warranted. The trial is registered at ClinicalTrials.gov (NCT04992390).

Temporal dynamics of trauma memory persistence.

Traumatic events lead to distressing memories, but such memories are made all the worse when they intrude to mind unbidden and recurrently. Intrusive memories and flashbacks after trauma are prominent in several mental disorders, including post-traumatic stress disorder and can persist for years. Critically, the reduction of intrusive memories provides a treatment target. While cognitive and descriptive models for psychological trauma exist, these lack formal quantitative structure and robust empirical validation. Here, using techniques from stochastic process theory, we develop a mechanistically driven, quantitative framework to extend understanding of the temporal dynamic processes of trauma memory. Our approach is to develop a probabilistic description of memory mechanisms to link to the broader goals of trauma treatment. We show how the marginal gains of treatments for intrusive memories can be enhanced as key properties (intervention strength and reminder strength) of the intervention and memory consolidation (probability memories are labile) vary. Parametrizing the framework with empirical data highlights that while emerging interventions to reduce occurrence of intrusive memories can be effective, counterintuitively, weakening multiple reactivation cues may help reduce intrusive memories more than would stronger cues. More broadly, the approach provides a quantitative framework for associating neural mechanisms of memory with broader cognitive processes.

Treating intrusive memories after trauma in healthcare workers: a Bayesian adaptive randomised trial developing an imagery-competing task intervention.

Intensive care unit (ICU) staff continue to face recurrent work-related traumatic events throughout the COVID-19 pandemic. Intrusive memories (IMs) of such traumatic events comprise sensory image-based memories. Harnessing research on preventing IMs with a novel behavioural intervention on the day of trauma, here we take critical next steps in developing this approach as a treatment for ICU staff who are already experiencing IMs days, weeks, or months post-trauma. To address the urgent need to develop novel mental health interventions, we used Bayesian statistical approaches to optimise a brief imagery-competing task intervention to reduce the number of IMs. We evaluated a digitised version of the intervention for remote, scalable delivery. We conducted a two-arm, parallel-group, randomised, adaptive Bayesian optimisation trial. Eligible participants worked clinically in a UK NHS ICU during the pandemic, experienced at least one work-related traumatic event, and at least three IMs in the week prior to recruitment. Participants were randomised to receive immediate or delayed (after 4 weeks) access to the intervention. Primary outcome was the number of IMs of trauma during week 4, controlling for baseline week. Analyses were conducted on an intention-to-treat basis as a between-group comparison. Prior to final analysis, sequential Bayesian analyses were conducted (n = 20, 23, 29, 37, 41, 45) to inform early stopping of the trial prior to the planned maximum recruitment (n = 150). Final analysis (n = 75) showed strong evidence for a positive treatment effect (Bayes factor, BF = 1.25 × 106): the immediate arm reported fewer IMs (median = 1, IQR = 0-3) than the delayed arm (median = 10, IQR = 6-16.5). With further digital enhancements, the intervention (n = 28) also showed a positive treatment effect (BF = 7.31). Sequential Bayesian analyses provided evidence for reducing IMs of work-related trauma for healthcare workers. This methodology also allowed us to rule out negative effects early, reduced the planned maximum sample size, and allowed evaluation of enhancements. Trial Registration NCT04992390 ( www.clinicaltrials.gov ).

A CRISPR endonuclease gene drive reveals distinct mechanisms of inheritance bias.

CRISPR/Cas gene drives can bias transgene inheritance through different mechanisms. Homing drives are designed to replace a wild-type allele with a copy of a drive element on the homologous chromosome. In Aedes aegypti, the sex-determining locus is closely linked to the white gene, which was previously used as a target for a homing drive element (wGDe). Here, through an analysis using this linkage we show that in males inheritance bias of wGDe did not occur by homing, rather through increased propagation of the donor drive element. We test the same wGDe drive element with transgenes expressing Cas9 with germline regulatory elements sds3, bgcn, and nup50. We only find inheritance bias through homing, even with the identical nup50-Cas9 transgene. We propose that DNA repair outcomes may be more context dependent than anticipated and that other previously reported homing drives may, in fact, bias their inheritance through other mechanisms.

Positive moods are all alike? Differential affect amplification effects of 'elated' versus 'calm' mental imagery in young adults reporting hypomanic-like experiences.

Positive mood amplification is a hallmark of the bipolar disorder spectrum (BPDS). We need better understanding of cognitive mechanisms contributing to such elevated mood. Generation of vivid, emotionally compelling mental imagery is proposed to act as an 'emotional amplifier' in BPDS. We used a positive mental imagery generation paradigm to manipulate affect in a subclinical BPDS-relevant sample reporting high (n = 31) vs. low (n = 30) hypomanic-like experiences on the Mood Disorder Questionnaire (MDQ). Participants were randomized to an 'elated' or 'calm' mental imagery condition, rating their momentary affect four times across the experimental session. We hypothesized greater affect increase in the high (vs. low) MDQ group assigned to the elated (vs. calm) imagery generation condition. We further hypothesized that affect increase in the high MDQ group would be particularly apparent in the types of affect typically associated with (hypo)mania, i.e., suggestive of high activity levels. Mixed model and time-series analysis showed that for the high MDQ group, affect increased steeply and in a sustained manner over time in the 'elated' imagery condition, and more shallowly in 'calm'. The low-MDQ group did not show this amplification effect. Analysis of affect clusters showed high-MDQ mood amplification in the 'elated' imagery condition was most pronounced for active affective states. This experimental model of BPDS-relevant mood amplification shows evidence that positive mental imagery drives changes in affect in the high MDQ group in a targeted manner. Findings inform cognitive mechanisms of mood amplification, and spotlight prevention strategies targeting elated imagery, while potentially retaining calm imagery to preserve adaptive positive emotionality.

Emerging patterns of fluoroquinolone resistance in Campylobacter jejuni in the UK [1998-2018].

Campylobacter jejuni (C.jejuni) is the most common causative agent of bacterial food poisoning worldwide and is known to be genetically highly diverse. C. jejuni is increasingly resistant to fluoroquinolone antibiotics, but very few studies have investigated variant-specific patterns of resistance across time. Here we use statistical modelling and clustering techniques to investigate patterns of fluoroquinolone resistance amongst 10,359 UK isolates from human disease sampled over 20 years. We observed six distinct patterns of fluoroquinolone sensitivity/resistance in C. jejuni across time, grouping by clonal complex (CC). Some CCs were fully resistant, some shifted from susceptible to resistant following a sigmoidal shape, and some remained susceptible over time. Our findings indicate that the fluoroquinolone resistance patterns of C. jejuni are complicated and cannot be analysed as a single species but divided into variant dynamics so that the factors driving resistance can be thoroughly investigated.

Daisy-chain gene drives: The role of low cut-rate, resistance mutations, and maternal deposition.

The introgression of genetic traits through gene drive may serve as a powerful and widely applicable method of biological control. However, for many applications, a self-perpetuating gene drive that can spread beyond the specific target population may be undesirable and preclude use. Daisy-chain gene drives have been proposed as a means of tuning the invasiveness of a gene drive, allowing it to spread efficiently into the target population, but be self-limiting beyond that. Daisy-chain gene drives are made up of multiple independent drive elements, where each element, except one, biases the inheritance of another, forming a chain. Under ideal inheritance biasing conditions, the released drive elements remain linked in the same configuration, generating copies of most of their elements except for the last remaining link in the chain. Through mathematical modelling of populations connected by migration, we have evaluated the effect of resistance alleles, different fitness costs, reduction in the cut-rate, and maternal deposition on two alternative daisy-chain gene drive designs. We find that the self-limiting nature of daisy-chain gene drives makes their spread highly dependent on the efficiency and fidelity of the inheritance biasing mechanism. In particular, reductions in the cut-rate and the formation of non-lethal resistance alleles can cause drive elements to lose their linked configuration. This severely reduces the invasiveness of the drives and allows for phantom cutting, where an upstream drive element cuts a downstream target locus despite the corresponding drive element being absent, creating and biasing the inheritance of additional resistance alleles. This phantom cutting can be mitigated by an alternative indirect daisy-chain design. We further find that while dominant fitness costs and maternal deposition reduce daisy-chain invasiveness, if overcome with an increased release frequency, they can reduce the spread of the drive into a neighbouring population.

Pavlovian threat conditioning can generate intrusive memories that persist over time.

Although Pavlovian threat conditioning has proven to be a useful translational model for the development of anxiety disorders, it remains unknown if this procedure can generate intrusive memories - a symptom of many anxiety-related disorders, and whether intrusions persist over time. Social support has been related to better adjustment after trauma however, experimental evidence regarding its effect on the development of anxiety-related symptoms is sparse. We had two aims: to test whether threat conditioning generates intrusive memories, and whether different social support interactions impacted expression of emotional memories. Non-clinical participants (n = 81) underwent threat conditioning to neutral stimuli. Participants were then assigned to a supportive, unsupportive, or no social interaction group, and asked to report intrusive memories for seven days. As predicted, threat conditioning can generate intrusions, with greater number of intrusions of CS+ (M = 2.35, SD = 3.09) than CS- (M = 1.39, SD = 2.17). Contrary to predictions, compared to no social interaction, supportive social interaction did not reduce, and unsupportive interaction did not increase skin conductance of learned threat or number of intrusions. Unsupportive interaction resulted in a relative difference in number of intrusions to CS + vs CS-, suggesting that unsupportive interaction might have increased image-based threat memories. Intrusions were still measurable one year after conditioning (one-year follow-up; n = 54), when individuals with higher trait anxiety and greater number of previous trauma experiences reported more intrusions. Our findings show that threat conditioning can create long-lasting intrusions, offering a novel experimental psychopathology model of intrusive memories with implications for both research on learning and clinical applications.

Life history and the evolutionary loss of parental care.

Parental care has been gained and lost evolutionarily multiple times. While many studies have focused on the origin of care, few have explored the evolutionary loss of care. Understanding the loss of parental care is important as the conditions that favour its loss will not necessarily be the opposite of those that favour the evolution of care. Evolutionary hysteresis (the case in which evolution depends on the history of a system) could create a situation in which it is relatively challenging to lose care once it has evolved. Here, using a mathematical approach, we explore the evolutionary loss of parental care in relation to basic life-history conditions. Our results suggest that parental care is most likely to be lost when egg and adult death rates are low, eggs mature quickly, and the level of care provided is high. We also predict evolutionary hysteresis with respect to egg maturation rate: as egg maturation rate decreases, it becomes increasingly more costly to lose care than to gain it. This suggests that once care is present, it will be particularly challenging for it to be lost if eggs develop slowly.

The Challenges in Developing Efficient and Robust Synthetic Homing Endonuclease Gene Drives.

Making discrete and precise genetic changes to wild populations has been proposed as a means of addressing some of the world's most pressing ecological and public health challenges caused by insect pests. Technologies that would allow this, such as synthetic gene drives, have been under development for many decades. Recently, a new generation of programmable nucleases has dramatically accelerated technological development. CRISPR-Cas9 has improved the efficiency of genetic engineering and has been used as the principal effector nuclease in different gene drive inheritance biasing mechanisms. Of these nuclease-based gene drives, homing endonuclease gene drives have been the subject of the bulk of research efforts (particularly in insects), with many different iterations having been developed upon similar core designs. We chart the history of homing gene drive development, highlighting the emergence of challenges such as unintended repair outcomes, "leaky" expression, and parental deposition. We conclude by discussing the progress made in developing strategies to increase the efficiency of homing endonuclease gene drives and mitigate or prevent unintended outcomes.

Mathematical modelling of the mosquito Aedes polynesiensis in a heterogeneous environment.

BACKGROUND: The mosquito Aedes polynesiensis inhabits Pacific islands and territories and transmits arboviruses and parasites. In the context of rapid environmental change, understanding the effects of environmental heterogeneity on mosquitoes is crucial. METHODS: First, empirical field data and remote sensing data were combined to model spatial heterogeneity in the environmental suitability for Ae. polynesiensis. Second, a model of mosquito population dynamics was applied to predict mosquito distributions over a heterogeneous landscape assuming different dispersal behaviours. Motu Tautau, French Polynesia, was used as a case study of the utility of this methodological approach. Ae. polynesiensis use land crab Cardisoma carnifex burrows for oviposition in French Polynesia; environmental suitability was therefore quantified using C. carnifex burrow density. RESULTS: Micro-regions with large Ae. polynesiensis populations facilitated by high C. carnifex burrow density were accurately captured by our methodology. Preferential dispersal towards oviposition sites promoted larger population sizes than non-preferential dispersal but did not offer greater resilience to environmental change. Reduced environmental suitability for Ae. polynesiensis resulted in spatially non-linear effects upon the mosquito distribution. CONCLUSIONS: Environmental change has complex spatial effects upon mosquito populations. Mosquito control strategies must carefully balance spatial effects with net effects.

Mechanisms of biodiversity between Campylobacter sequence types in a flock of broiler-breeder chickens.

Commercial poultry flocks frequently harbor the dangerous bacterial pathogen Campylobacter. As exclusion efforts frequently fail, there is interest in potential ecologically informed solutions. A long-term study of Campylobacter sequence types was used to investigate the competitive framework of the Campylobacter metacommunity and understand how multiple sequence types simultaneously co-occur in a flock of chickens. A combination of matrix and patch-occupancy models was used to estimate parameters describing the competition, transmission, and mortality of each sequence type. It was found that Campylobacter sequence types form a strong hierarchical framework within a flock of chickens and occupied a broad spectrum of transmission-mortality trade-offs. Upon further investigation of how biodiversity is thus maintained within the flock, it was found that the demographic capabilities of Campylobacter, such as mortality and transmission, could not explain the broad biodiversity of sequence types seen, suggesting that external factors such as host-bird health and seasonality are important elements in maintaining biodiversity of Campylobacter sequence types.

Catastrophe risk can accelerate unlikely evolutionary transitions.

Intelligent life has emerged late in Earth's habitable lifetime, and required a preceding series of key evolutionary transitions. A simple model (the Carter model) explains the late arrival of intelligent life by positing these evolutionary transitions were exceptionally unlikely 'critical steps'. An alternative model (the neocatastrophism hypothesis) proposes that intelligent life was delayed by frequent catastrophes that served to set back evolutionary innovation. Here, we generalize the Carter model and explore this hypothesis by including catastrophes that can 'undo' an evolutionary transition. Introducing catastrophes or evolutionary dead ends can create situations in which critical steps occur rapidly or in clusters, suggesting that past estimates of the number of critical steps could be underestimated. If catastrophes affect complex life more than simple life, the critical steps will also exhibit a pattern of acceleration towards the present, suggesting that the increase in biological complexity over the past 500 Myr could reflect previously overlooked evolutionary transitions. Furthermore, our results have implications for understanding the different explanations (critical steps versus neo-catastrophes) for the evolution of intelligent life and the so-called Fermi paradox-the observation that intelligent life appears rare in the observable Universe.

Evaluating strategies for spatial allocation of vaccines based on risk and centrality.

When vaccinating a large population in response to an invading pathogen, it is often necessary to prioritize some individuals to be vaccinated first. One way to do this is to choose individuals to vaccinate based on their location. Methods for this prioritization include strategies that target those regions most at risk of importing the pathogen, and strategies that target regions with high centrality on the travel network. We use a simple infectious disease epidemic model to compare a risk-targeting strategy to two different centrality-targeting strategies based on betweenness centrality and random walk percolation centrality, respectively. We find that the relative effectiveness of these strategies in reducing the total number of infections varies with the basic reproduction number of the pathogen, travel rates, structure of the travel network and vaccine availability. We conclude that when a pathogen has high spreading capacity, or when vaccine availability is limited, centrality-targeting strategies should be considered as an alternative to the more commonly used risk-targeting strategies.

Incorporating effects of age on energy dynamics predicts nonlinear maternal allocation patterns in iteroparous animals.

Iteroparous parents face a trade-off between allocating current resources to reproduction versus maximizing survival to produce further offspring. Parental allocation varies across age and follows a hump-shaped pattern across diverse taxa, including mammals, birds and invertebrates. This nonlinear allocation pattern lacks a general theoretical explanation, potentially because most studies focus on offspring number rather than quality and do not incorporate uncertainty or age-dependence in energy intake or costs. Here, we develop a life-history model of maternal allocation in iteroparous animals. We identify the optimal allocation strategy in response to stochasticity when energetic costs, feeding success, energy intake and environmentally driven mortality risk are age-dependent. As a case study, we use tsetse, a viviparous insect that produces one offspring per reproductive attempt and relies on an uncertain food supply of vertebrate blood. Diverse scenarios generate a hump-shaped allocation when energetic costs and energy intake increase with age and also when energy intake decreases and energetic costs increase or decrease. Feeding success and environmentally driven mortality risk have little influence on age-dependence in allocation. We conclude that ubiquitous evidence for age-dependence in these influential traits can explain the prevalence of nonlinear maternal allocation across diverse taxonomic groups.

BugSplit enables genome-resolved metagenomics through highly accurate taxonomic binning of metagenomic assemblies.

A large gap remains between sequencing a microbial community and characterizing all of the organisms inside of it. Here we develop a novel method to taxonomically bin metagenomic assemblies through alignment of contigs against a reference database. We show that this workflow, BugSplit, bins metagenome-assembled contigs to species with a 33% absolute improvement in F1-score when compared to alternative tools. We perform nanopore mNGS on patients with COVID-19, and using a reference database predating COVID-19, demonstrate that BugSplit's taxonomic binning enables sensitive and specific detection of a novel coronavirus not possible with other approaches. When applied to nanopore mNGS data from cases of Klebsiella pneumoniae and Neisseria gonorrhoeae infection, BugSplit's taxonomic binning accurately separates pathogen sequences from those of the host and microbiota, and unlocks the possibility of sequence typing, in silico serotyping, and antimicrobial resistance prediction of each organism within a sample. BugSplit is available at https://bugseq.com/academic .