Two-Photon FRET/FLIM Imaging of Cerebral Neurons.

Two-photon FRET (Förster resonance energy transfer) and FLIM (fluorescence lifetime imaging microscopy) enable the detection of FRET changes of fluorescence reporters in deep brain tissues, which provide a valuable approach for monitoring target molecular dynamics and functions. Here, we describe two-photon FRET and FLIM imaging techniques that allow us to visualize endogenous and optogenetically induced cAMP dynamics in living neurons with genetically engineered FRET-based cAMP reporters.

Fear memory regulation by the cAMP signaling pathway as an index of reexperiencing symptoms in posttraumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder associated with traumatic memory, yet its etiology remains unclear. Reexperiencing symptoms are specific to PTSD compared to other anxiety-related disorders. Importantly, reexperiencing can be mimicked by retrieval-related events of fear memory in animal models of traumatic memory. Recent studies revealed candidate PTSD-associated genes that were related to the cyclic adenosine monophosphate (cAMP) signaling pathway. Here, we demonstrate the tight linkage between facilitated cAMP signaling and PTSD by analyzing loss- and gain-of-cAMP signaling effects on fear memory in mice and the transcriptomes of fear memory-activated mice and female PTSD patients with reexperiencing symptoms. Pharmacological and optogenetic upregulation or downregulation of cAMP signaling transduction enhanced or impaired, respectively, the retrieval and subsequent maintenance of fear memory in mice. In line with these observations, integrative mouse and human transcriptome analysis revealed the reduced mRNA expression of phosphodiesterase 4B (PDE4B), an enzyme that degrades cAMP, in the peripheral blood of PTSD patients showing more severe reexperiencing symptoms and the mouse hippocampus after fear memory retrieval. Importantly, more severe reexperiencing symptoms and lower PDE4B mRNA levels were correlated with decreased DNA methylation of a locus within PDE4B, suggesting the involvement of methylation in the mechanism of PTSD. These findings raise the possibility that the facilitation of cAMP signaling mediating the downregulation of PDE4B expression enhances traumatic memory, thereby playing a key role in the reexperiencing symptoms of PTSD patients as a functional index of these symptoms.

Neuronal SNAP-23 is critical for synaptic plasticity and spatial memory independently of NMDA receptor regulation.

SNARE-mediated membrane fusion plays a crucial role in presynaptic vesicle exocytosis and also in postsynaptic receptor delivery. The latter is considered particularly important for synaptic plasticity and learning and memory, yet the identity of the key SNARE proteins remains elusive. Here, we investigate the role of neuronal synaptosomal-associated protein-23 (SNAP-23) by analyzing pyramidal-neuron specific SNAP-23 conditional knockout (cKO) mice. Electrophysiological analysis of SNAP-23 deficient neurons using acute hippocampal slices showed normal basal neurotransmission in CA3-CA1 synapses with unchanged AMPA and NMDA currents. Nevertheless, we found theta-burst stimulation-induced long-term potentiation (LTP) was vastly diminished in SNAP-23 cKO slices. Moreover, unlike syntaxin-4 cKO mice where both basal neurotransmission and LTP decrease manifested changes in a broad set of behavioral tasks, deficits of SNAP-23 cKO are more limited to spatial memory. Our data reveal that neuronal SNAP-23 is selectively crucial for synaptic plasticity and spatial memory without affecting basal glutamate receptor function.

When might host heterogeneity drive the evolution of asymptomatic, pandemic coronaviruses?

Controlling many infectious diseases, including SARS-Coronavirus-2 (SARS-CoV-2), requires surveillance followed by isolation, contact-tracing and quarantining. These interventions often begin by identifying symptomatic individuals. However, actively removing pathogen strains causing symptomatic infections may inadvertently select for strains less likely to cause symptomatic infections. Moreover, a pathogen's fitness landscape is structured around a heterogeneous host pool; uneven surveillance efforts and distinct transmission risks across host classes can meaningfully alter selection pressures. Here, we explore this interplay between evolution caused by disease control efforts and the evolutionary consequences of host heterogeneity. Using an evolutionary epidemiology model parameterized for coronaviruses, we show that intense symptoms-driven disease control selects for asymptomatic strains, particularly when these efforts are applied unevenly across host groups. Under these conditions, increasing quarantine efforts have diverging effects. If isolation alone cannot eradicate, intensive quarantine efforts combined with uneven detections of asymptomatic infections (e.g., via neglect of some host classes) can favor the evolution of asymptomatic strains. We further show how, when intervention intensity depends on the prevalence of symptomatic infections, higher removal efforts (and isolating symptomatic cases in particular) more readily select for asymptomatic strains than when these efforts do not depend on prevalence. The selection pressures on pathogens caused by isolation and quarantining likely lie between the extremes of no intervention and thoroughly successful eradication. Thus, analyzing how different public health responses can select for asymptomatic pathogen strains is critical for identifying disease suppression efforts that can effectively manage emerging infectious diseases. Supplementary Information: The online version contains supplementary material available at 10.1007/s11071-022-07548-7.

A critical assessment of the detailed Aedes aegypti simulation model Skeeter Buster 2 using field experiments of indoor insecticidal control in Iquitos, Peru.

The importance of mosquitoes in human pathogen transmission has motivated major research efforts into mosquito biology in pursuit of more effective vector control measures. Aedes aegypti is a particular concern in tropical urban areas, where it is the primary vector of numerous flaviviruses, including the yellow fever, Zika, and dengue viruses. With an anthropophilic habit, Ae. aegypti prefers houses, human blood meals, and ovipositioning in water-filled containers. We hypothesized that this relatively simple ecological niche should allow us to predict the impacts of insecticidal control measures on mosquito populations. To do this, we use Skeeter Buster 2 (SB2), a stochastic, spatially explicit, mechanistic model of Ae. aegypti population biology. SB2 builds on Skeeter Buster, which reproduced equilibrium dynamics of Ae. aegypti in Iquitos, Peru. Our goal was to validate SB2 by predicting the response of mosquito populations to perturbations by indoor insecticidal spraying and widespread destructive insect surveys. To evaluate SB2, we conducted two field experiments in Iquitos, Peru: a smaller pilot study in 2013 (S-2013) followed by a larger experiment in 2014 (L-2014). Here, we compare model predictions with (previously reported) empirical results from these experiments. In both simulated and empirical populations, repeated spraying yielded substantial yet temporary reductions in adult densities. The proportional effects of spraying were broadly comparable between simulated and empirical results, but we found noteworthy differences. In particular, SB2 consistently over-estimated the proportion of nulliparous females and the proportion of containers holding immature mosquitoes. We also observed less temporal variation in simulated surveys of adult abundance relative to corresponding empirical observations. Our results indicate the presence of ecological heterogeneities or sampling processes not effectively represented by SB2. Although additional empirical research could further improve the accuracy and precision of SB2, our results underscore the importance of non-linear dynamics in the response of Ae. aegypti populations to perturbations, and suggest general limits to the fine-grained predictability of its population dynamics over space and time.

Eco-evolutionary dynamics of interference competition.

Theorists have identified several mechanisms through which species that compete exploitatively for resources could coexist. By contrast, under the current theory, interference competitors could coexist only in rare circumstances. Yet, some types of interference competition, such as interspecific territoriality, are common. This mismatch between theory and nature inspired us to model interference competition in an eco-evolutionary framework. We based the model on the life cycle of territorial birds and ran simulations to examine whether natural selection could rescue a superior interference competitor from extinction without driving a superior exploitative competitor extinct. We found that coexistence between interference competitors can occur over a wide range of ecologically plausible scenarios, and up to the highest levels of resource overlap. An important caveat is that coexistence requires the species to co-evolve. Reductions in population size and levels of genetic variation could destabilise coexistence between interference competitors, and thereby increase extinction rates over current estimates.

Mapping climate change's impact on cholera infection risk in Bangladesh.

Several studies have investigated how Vibrio cholerae infection risk changes with increased rainfall, temperature, and water pH levels for coastal Bangladesh, which experiences seasonal surges in cholera infections associated with heavy rainfall events. While coastal environmental conditions are understood to influence V. cholerae propagation within brackish waters and transmission to and within human populations, it remains unknown how changing climate regimes impact the risk for cholera infection throughout Bangladesh. To address this, we developed a random forest species distribution model to predict the occurrence probability of cholera incidence within Bangladesh for 2015 and 2050. We developed a random forest model trained on cholera incidence data and spatial environmental raster data to be predicted to environmental data for the year of training (2015) and 2050. From our model's predictions, we generated risk maps for cholera occurrence for 2015 and 2050. Our best-fitting model predicted cholera occurrence given elevation and distance to water. Generally, we find that regions within every district in Bangladesh experience an increase in infection risk from 2015 to 2050. We also find that although cells of high risk cluster along the coastline predominantly in 2015, by 2050 high-risk areas expand from the coast inland, conglomerating around surface waters across Bangladesh, reaching all but the northwestern-most district. Mapping the geographic distribution of cholera infections given projected environmental conditions provides a valuable tool for guiding proactive public health policy tailored to areas most at risk of future disease outbreaks.

Advancing phage therapy through the lens of virus host-breadth and emergence potential.

Phages are viruses that specifically infect bacteria, and their biodiversity contributes to historical and current development of phage therapy to treat myriad bacterial infections. Phage therapy holds promise as an alternative to failing chemical antibiotics, but there are benefits and costs of this technology. Here, we review the rich history of phage therapy, highlighting reasons (often political) why it was widely rejected by Western medicine until recently. One longstanding idea involves mixing different phages together in cocktails, to increase the probability of killing target pathogenic bacteria without pre-screening for phage susceptibility. By challenging 30 lytic phages to infect 14 strains of the bacteria Pseudomonas aeruginosa, we showed that some phages were "generalists" with broad host-ranges, emphasizing that extreme host-specificity of phages was not necessarily a liability. Using a "greedy algorithm" analysis, we identified the best cocktail mixture of phages to achieve broad bacteria killing. Additionally, we review how virus host-range can evolve and connect lessons learned from virus emergence-including contributions of elevated virus mutation rates in promoting emergence and virus evolutionary transitions from specialized to generalized host-use-as cautionary tales for avoiding risk of "off-target" phage emergence on commensal bacteria in microbiomes. Throughout, we highlight how fundamental understanding of virus ecology and evolution is vital for developing phage therapy; heeding these principles should help in designing therapeutic strategies that do not recapitulate consequences of virus selection to emerge on novel hosts.

After the honeymoon, the divorce: Unexpected outcomes of disease control measures against endemic infections.

The lack of effective vaccines for many endemic diseases often forces policymakers to rely on non-immunizing control measures, such as vector control, to reduce the massive burden of these diseases. Controls can have well-known counterintuitive effects on endemic infections, including the honeymoon effect, in which partially effective controls cause not only a greater initial reduction in infection than expected, but also large outbreaks during control resulting from accumulation of susceptibles. Unfortunately, many control measures cannot be maintained indefinitely, and the results of cessation are poorly understood. Here, we examine the results of stopped or failed non-immunizing control measures in endemic settings. By using a mathematical model to compare the cumulative number of cases expected with and without control, we show that deployment of control can lead to a larger total number of infections, counting from the time that control started, than without any control-the divorce effect. This result is directly related to the population-level loss of immunity resulting from non-immunizing controls and is seen in a variety of models when non-immunizing controls are used against an infection that confers immunity. Finally, we examine three control plans for minimizing the magnitude of the divorce effect in seasonal infections and show that they are incapable of eliminating the divorce effect. While we do not suggest stopping control programs that rely on non-immunizing controls, our results strongly argue that the accumulation of susceptibility should be considered before deploying such controls against endemic infections when indefinite use of the control is unlikely. We highlight that our results are particularly germane to endemic mosquito-borne infections, such as dengue virus, both for routine management involving vector control and for field trials of novel control approaches, and in the context of non-pharmaceutical interventions aimed at COVID-19.

Optogenetic Manipulation of Postsynaptic cAMP Using a Novel Transgenic Mouse Line Enables Synaptic Plasticity and Enhances Depolarization Following Tetanic Stimulation in the Hippocampal Dentate Gyrus.

cAMP is a positive regulator tightly involved in certain types of synaptic plasticity and related memory functions. However, its spatiotemporal roles at the synaptic and neural circuit levels remain elusive. Using a combination of a cAMP optogenetics approach and voltage-sensitive dye (VSD) imaging with electrophysiological recording, we define a novel capacity of postsynaptic cAMP in enabling dentate gyrus long-term potentiation (LTP) and depolarization in acutely prepared murine hippocampal slices. To manipulate cAMP levels at medial perforant path to granule neuron (MPP-DG) synapses by light, we generated transgenic (Tg) mice expressing photoactivatable adenylyl cyclase (PAC) in DG granule neurons. Using these Tg(CMV-Camk2a-RFP/bPAC)3Koka mice, we recorded field excitatory postsynaptic potentials (fEPSPs) from MPP-DG synapses and found that photoactivation of PAC during tetanic stimulation enabled synaptic potentiation that persisted for at least 30 min. This form of LTP was induced without the need for GABA receptor blockade that is typically required for inducing DG plasticity. The paired-pulse ratio (PPR) remained unchanged, indicating the cAMP-dependent LTP was likely postsynaptic. By employing fast fluorescent voltage-sensitive dye (VSD: di-4-ANEPPS) and fluorescence imaging, we found that photoactivation of the PAC actuator enhanced the intensity and extent of dentate gyrus depolarization triggered following tetanic stimulation. These results demonstrate that the elevation of cAMP in granule neurons is capable of rapidly enhancing synaptic strength and neuronal depolarization. The powerful actions of cAMP are consistent with this second messenger having a critical role in the regulation of synaptic function.

Predicting evolutionary responses to interspecific interference in the wild.

Many interspecifically territorial species interfere with each other reproductively, and in some cases, aggression towards heterospecifics may be an adaptive response to interspecific mate competition. This hypothesis was recently formalised in an agonistic character displacement (ACD) model which predicts that species should evolve to defend territories against heterospecific rivals above a threshold level of reproductive interference. To test this prediction, we parameterised the model with field estimates of reproductive interference for 32 sympatric damselfly populations and ran evolutionary simulations. Asymmetries in reproductive interference made the outcome inherently unpredictable in some cases, but 80% of the model's stable outcomes matched levels of heterospecific aggression in the field, significantly exceeding chance expectations. In addition to bolstering the evidence for ACD, this paper introduces a new, predictive approach to testing character displacement theory that, if applied to other systems, could help in resolving long-standing questions about the importance of character displacement processes in nature.

Managing the emergence of pathogen resistance via spatially targeted antimicrobial use.

From agriculture to public health to civil engineering, managing antimicrobial resistance presents a considerable challenge. The dynamics underlying resistance evolution reflect inherently spatial processes. Resistant pathogen strains increase in frequency when a strain that emerges in one locale can spread and replace pathogen subpopulations formerly sensitive to the antimicrobial agent. Moreover, the strength of selection for antimicrobial resistance is in part governed by the extent of antimicrobial use. Thus, altering how antimicrobials are used across a landscape can potentially shift the spatial context governing the dynamics of antimicrobial resistance and provide a potent management tool. Here, we model how the efficacy of adjusting antimicrobial use over space to manage antimicrobial resistance is mediated by competition among pathogen strains and the topology of pathogen metapopulations. For several pathogen migration scenarios, we derive critical thresholds for the spatial extent of antimicrobial use below which resistance cannot emerge, and relate these thresholds to (a) the ability to eradicate antimicrobial-sensitive pathogens locally and (b) the strength of the trade-off between resistance ability and competitive performance where antimicrobial use is absent. We find that in metapopulations where patches differ in connectedness, constraining antimicrobial use across space to mitigate resistance evolution only works if the migration of the resistant pathogen is modest; yet, this situation is reversed if the resistant strain has a high colonization rate, with variably connected metapopulations exhibiting less sensitivity to reducing antimicrobial use across space. Furthermore, when pathogens are alternately exposed to sites with and without the antimicrobial, bottlenecking resistant strains through sites without an antimicrobial is only likely to be effective under a strong competition-resistance trade-off. We therefore identify life-history constraints that are likely to suggest which pathogens can most effectively be controlled by a spatially targeted antimicrobial regime. We discuss implications of our results for managing and thinking about antimicrobial resistance evolution in spatially heterogeneous contexts.

Regulation of actin dynamics during structural plasticity of dendritic spines: Signaling messengers and actin-binding proteins.

Activity-dependent plasticity of synaptic structure and function plays an essential role in neuronal development and in cognitive functions including learning and memory. The formation, maintenance and modulation of dendritic spines are mainly controlled by the dynamics of actin filaments (F-actin) through interaction with various actin-binding proteins (ABPs) and postsynaptic signaling messengers. Induction of long-term potentiation (LTP) triggers a cascade of events involving Ca2+ signaling, intracellular pathways such as cAMP and cGMP, and regulation of ABPs such as CaMKII, Cofilin, Aip1, Arp2/3, α-actinin, Profilin and Drebrin. We review here how these ABPs modulate the rate of assembly, disassembly, stabilization and bundling of F-actin during LTP induction. We highlight the crucial role that CaMKII exerts in both functional and structural plasticity by directly coupling Ca2+ signaling with F-actin dynamics through the ß subunit. Moreover, we show how cAMP and cGMP second messengers regulate postsynaptic structural potentiation. Brain disorders such as Alzheimer's disease, schizophrenia or autism, are associated with alterations in the regulation of F-actin dynamics by these ABPs and signaling messengers. Thus, a better understanding of the molecular mechanisms controlling actin cytoskeleton can provide cues for the treatment of these disorders.

Crucial Role of Postsynaptic Syntaxin 4 in Mediating Basal Neurotransmission and Synaptic Plasticity in Hippocampal CA1 Neurons.

Trafficking of neurotransmitter receptors on postsynaptic membranes is critical for basal neurotransmission and synaptic plasticity, yet the underlying mechanisms remain elusive. Here, we investigated the role of syntaxin 4 in postsynaptic hippocampal CA1 neurons by analyzing conditional knockout (syntaxin 4 cKO) mice. We show that syntaxin 4 cKO resulted in reduction of basal neurotransmission without changes in paired-pulse ratios. Both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptor-mediated charge transfers were diminished. Patch-clamp experiments revealed that amplitudes, but not frequencies, of spontaneous excitatory postsynaptic currents are reduced. Syntaxin 4 knockout (KO) caused drastic reduction in expression of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptors in cultured hippocampal neurons. Furthermore, cKO caused defects in theta-burst stimulation induced long-term potentiation and spatial learning as assessed by a water maze task, indicating that synaptic plasticity was altered. Our data reveal a crucial role of syntaxin 4 in trafficking of ionotropic glutamate receptors that are essential for basal neurotransmission, synaptic plasticity, and spatial memory.

Efficacy of Aedes aegypti control by indoor Ultra Low Volume (ULV) insecticide spraying in Iquitos, Peru.

BACKGROUND: Aedes aegypti is a primary vector of dengue, chikungunya, Zika, and urban yellow fever viruses. Indoor, ultra low volume (ULV) space spraying with pyrethroid insecticides is the main approach used for Ae. aegypti emergency control in many countries. Given the widespread use of this method, the lack of large-scale experiments or detailed evaluations of municipal spray programs is problematic. METHODOLOGY/PRINCIPAL FINDINGS: Two experimental evaluations of non-residual, indoor ULV pyrethroid spraying were conducted in Iquitos, Peru. In each, a central sprayed sector was surrounded by an unsprayed buffer sector. In 2013, spray and buffer sectors included 398 and 765 houses, respectively. Spraying reduced the mean number of adults captured per house by ~83 percent relative to the pre-spray baseline survey. In the 2014 experiment, sprayed and buffer sectors included 1,117 and 1,049 houses, respectively. Here, the sprayed sector's number of adults per house was reduced ~64 percent relative to baseline. Parity surveys in the sprayed sector during the 2014 spray period indicated an increase in the proportion of very young females. We also evaluated impacts of a 2014 citywide spray program by the local Ministry of Health, which reduced adult populations by ~60 percent. In all cases, adult densities returned to near-baseline levels within one month. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that densities of adult Ae. aegypti can be reduced by experimental and municipal spraying programs. The finding that adult densities return to approximately pre-spray densities in less than a month is similar to results from previous, smaller scale experiments. Our results demonstrate that ULV spraying is best viewed as having a short-term entomological effect. The epidemiological impact of ULV spraying will need evaluation in future trials that measure capacity of insecticide spraying to reduce human infection or disease.

Interplay of enzymatic and structural functions of CaMKII in long-term potentiation.

Since the discovery of long-term potentiation (LTP) about a half-century ago, Ca2+ /CaM-dependent protein kinase II (CaMKII) has been one of the most extensively studied components of the molecular machinery that regulate plasticity. This unique dodecameric kinase complex plays pivotal roles in LTP by phosphorylating substrates through elaborate regulatory mechanisms, and is known to be both necessary and sufficient for LTP. In addition to acting as a kinase, CaMKII has been postulated to have structural roles because of its extraordinary abundance and diverse interacting partners. It now is becoming clear that these two functions of CaMKII cooperate closely for the induction of both functional and structural synaptic plasticity of dendritic spines. Because of its extraordinary abundance within neuronal cells, calmodulin kinase CaMKII has been believed to act as a structural protein as well as an enzyme during synaptic plasticity. In this review, we summarized studies in CaMKII field and provide an insight into how enzymatic and structural functions of CaMKII cooperate with each other for long-term potentiation (LTP) in neurons. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases".

Integrating Transgenic Vector Manipulation with Clinical Interventions to Manage Vector-Borne Diseases.

Many vector-borne diseases lack effective vaccines and medications, and the limitations of traditional vector control have inspired novel approaches based on using genetic engineering to manipulate vector populations and thereby reduce transmission. Yet both the short- and long-term epidemiological effects of these transgenic strategies are highly uncertain. If neither vaccines, medications, nor transgenic strategies can by themselves suffice for managing vector-borne diseases, integrating these approaches becomes key. Here we develop a framework to evaluate how clinical interventions (i.e., vaccination and medication) can be integrated with transgenic vector manipulation strategies to prevent disease invasion and reduce disease incidence. We show that the ability of clinical interventions to accelerate disease suppression can depend on the nature of the transgenic manipulation deployed (e.g., whether vector population reduction or replacement is attempted). We find that making a specific, individual strategy highly effective may not be necessary for attaining public-health objectives, provided suitable combinations can be adopted. However, we show how combining only partially effective antimicrobial drugs or vaccination with transgenic vector manipulations that merely temporarily lower vector competence can amplify disease resurgence following transient suppression. Thus, transgenic vector manipulation that cannot be sustained can have adverse consequences-consequences which ineffective clinical interventions can at best only mitigate, and at worst temporarily exacerbate. This result, which arises from differences between the time scale on which the interventions affect disease dynamics and the time scale of host population dynamics, highlights the importance of accounting for the potential delay in the effects of deploying public health strategies on long-term disease incidence. We find that for systems at the disease-endemic equilibrium, even modest perturbations induced by weak interventions can exhibit strong, albeit transient, epidemiological effects. This, together with our finding that under some conditions combining strategies could have transient adverse epidemiological effects suggests that a relatively long time horizon may be necessary to discern the efficacy of alternative intervention strategies.

Generalized selection to overcome innate immunity selects for host breadth in an RNA virus.

Virus-host coevolution has selected for generalized host defense against viruses, exemplified by interferon production/signaling and other innate immune function in eukaryotes such as humans. Although cell-surface binding primarily limits virus infection success, generalized adaptation to counteract innate immunity across disparate hosts may contribute to RNA virus emergence potential. We examined this idea using vesicular stomatitis virus (VSV) populations previously evolved on strictly immune-deficient (HeLa) cells, strictly immune competent (MDCK) cells, or on alternating deficient/competent cells. By measuring viral fitness in unselected human cancer cells of differing innate immunity, we confirmed that HeLa-adapted populations were specialized for innate immune-deficient hosts, whereas MDCK-adapted populations were relatively more generalized for fitness on hosts of differing innate immune capacity and of different species origin. We also confirmed that HeLa-evolved populations maintained fitness in immune-deficient nonhuman primate cells. These results suggest that innate immunity is more prominent than host species in determining viral fitness at the host-cell level. Finally, our prediction was inexact that selection on alternating deficient/competent hosts should produce innate viral generalists. Rather, fitness differences among alternating host-evolved VSV populations indicated variable capacities to evade innate immunity. Our results suggest that the evolutionary history of innate immune selection can affect whether RNA viruses evolve greater host-breadth.

The dynamics of strangling among forest trees.

Strangler trees germinate and grow on other trees, eventually enveloping and potentially even girdling their hosts. This allows them to mitigate fitness costs otherwise incurred by germinating and competing with other trees on the forest floor, as well as minimize risks associated with host tree-fall. If stranglers can themselves host other strangler trees, they may not even seem to need non-stranglers to persist. Yet despite their high fitness potential, strangler trees neither dominate the communities in which they occur nor is the strategy particularly common outside of figs (genus Ficus). Here we analyze how dynamic interactions between strangling and non-strangling trees can shape the adaptive landscape for strangling mutants and mutant trees that have lost the ability to strangle. We find a threshold which strangler germination rates must exceed for selection to favor the evolution of strangling, regardless of how effectively hemiepiphytic stranglers may subsequently replace their hosts. This condition describes the magnitude of the phenotypic displacement in the ability to germinate on other trees necessary for invasion by a mutant tree that could potentially strangle its host following establishment as an epiphyte. We show how the relative abilities of strangling and non-strangling trees to occupy empty sites can govern whether strangling is an evolutionarily stable strategy, and obtain the conditions for strangler coexistence with non-stranglers. We then elucidate when the evolution of strangling can disrupt stable coexistence between commensal epiphytic ancestors and their non-strangling host trees. This allows us to highlight parallels between the invasion fitness of strangler trees arising from commensalist ancestors, and cases where strangling can arise in concert with the evolution of hemiepiphytism among free-standing ancestors. Finally, we discuss how our results can inform the evolutionary ecology of antagonistic interactions more generally.

A Temporary Gating of Actin Remodeling during Synaptic Plasticity Consists of the Interplay between the Kinase and Structural Functions of CaMKII.

The structural modification of dendritic spines plays a critical role in synaptic plasticity. CaMKII is a pivotal molecule involved in this process through both kinase-dependent and independent structural functions, but the respective contributions of these two functions to the synaptic plasticity remain unclear. We demonstrate that the transient interplay between the kinase and structural functions of CaMKII during the induction of synaptic plasticity temporally gates the activity-dependent modification of the actin cytoskeleton. Inactive CaMKII binds F-actin, thereby limiting access of actin-regulating proteins to F-actin and stabilizing spine structure. CaMKII-activating stimuli trigger dissociation of CaMKII from F-actin through specific autophosphorylation reactions within the F-actin binding region and permits F-actin remodeling by regulatory proteins followed by reassociation and restabilization. Blocking the autophosphorylation impairs both functional and structural plasticity without affecting kinase activity. These results underpin the importance of the interplay between the kinase and structural functions of CaMKII in defining a time window permissive for synaptic plasticity.