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Cohen, J.

Publications and source records attributed to Cohen, J..

At least 37 records · Page 2Linked to original sources

Continental species distribution and biodiversity predictions depend on modeling grain

As global change accelerates, accurate predictions of species distributions and biodiversity patterns are critical to prevent population declines and biodiversity loss. However, at continental and global scales, these predictions are often derived from species distribution models (SDMs) fit at coarse spatial grains uninformed by ecological processes. Coarse-grain models may systematically bias predictions of distributions and biodiversity if they are consistently over- or under-estimating area with suitable habitat, and this bias may intensify in regions with heterogenous landscapes or with poor data coverage. To test this, we fit presence-absence SDMs characterizing both the summer and winter distributions of 572 North American bird species - nearly the entire avian diversity of the US and Canada - across five spatial grains from 1 to 50 km, using observations from the eBird citizen science initiative. We find that across both seasons, models fit at 1 km performed better under cross-validation than those at coarser scales and more accurately predicted species presences and absences at local sites. Coarser-grain models, including models fit at 3 km, consistently under-predicted range area relative to 1 km models, suggesting that coarse-grain estimates of distributions could be missing important habitat. This bias intensified during summer (83% of species) when many birds have smaller operational scales via localized home ranges and greater habitat specificity while breeding. Biases were greatest in heterogenous desert and scrubland regions and lowest in more homogenous boreal forest and taiga-dominated regions. When aggregating distributions to produce continental biodiversity predictions, coarse-grain models overpredicted diversity in the west and underpredicted it in the great plains, prairie pothole region and boreal/taiga zones. The modern availability of high-performance computing and high-resolution observational and environmental data provides opportunities to improve continental predictions of species distributions and biodiversity.

ecology↗

Critical reproductive behaviors in Scaled Quail and Northern Bobwhite are affected by thermal variability and mean temperature

Animals can respond differently to shifting thermal variability versus thermal averages, both of which are changing due to climate warming. How these thermal variables affect parental care behaviors can reveal the ability of parents to modify their behaviors to meet the competing demands of their offsprings thermal needs and self-maintenance, which becomes critical in suboptimal thermal conditions. Further, the time frame used to examine the interplay between temperature and behavioral shifts (e.g., seasonal patterns in care vs. drivers of individual care decisions) can provide different information about the plasticity of parental care behavior. We investigated the relationship between thermal means, thermal variability, and incubation behaviors across multiple timescales in Scaled Quail and Northern Bobwhite. Both species decreased off-bout length during periods of high thermal variability, a novel finding among studies of avian parental behavior. Further relationships between thermal endpoints (mean vs. variation) and behavior differed depending on the temporal scale. For instance, total daily time spent off the nest was not influenced by daily average temperature, yet individual off-bout duration increased with increasing average temperature in the two hours prior to the off-bout. These results provide evidence that thermal-behavioral relationships differ across scales and likely represent a birds ability to modify their incubation strategy to rapidly respond to the immediate thermal environment (altering individual off-bout length based on temperature) to meet self-maintenance needs while resulting in a similar outcome for their nest (total daily off-bout time). However, longer off-bout durations during high temperature events can come with reproductive costs, sometimes resulting in acute offspring mortality when eggs or chicks experience lethal temperatures.

animal behavior and cognition↗

Structural covariation between cerebellum and cerebral cortex is atypically modulated by thalamus in autism spectrum disorder

Despite its strong interconnectivity with the cerebral cortex, the influence of the human cerebellum on neocortical structure and its role in the development of neuropsychiatric disorders is unclear. Because cerebellar damage in early postnatal life creates a high risk for autism spectrum disorder (ASD), we investigated inter-relationships in cerebello-cerebral morphology. Leveraging a large structural brain MRI dataset in neurotypical children (n=375) and those diagnosed with ASD (n=373), we examined whether volumetric variation in cerebellar structure across individuals was correlated with neocortical variation during development, modeling the thalamus as a moderating coupling factor. We found negative covariation between cerebellar cortical regions and thalamic/sensorimotor neocortical regions, and positive covariation between thalamic and sensorimotor neocortical regions. This pattern aligned with the major disynaptic path of cerebellar inhibition to thalamocortical excitation. Examining the dependence of this structural covariation on ASD diagnosis, we found that neurotypical and ASD children displayed inverted hemispheric biases. In ASD, the thalamus moderated structural associations between the left cerebellum and right sensorimotor cortex. For neurotypical children, right cerebellum and left sensorimotor cortex were coupled. Notably, structural coupling between cerebellum, thalamus, and neocortex was strongest in younger childhood and waned by early adolescence, a time during which behavioral differences were smallest between typically developing and autistic children. In addition to the sensorimotor cortex, cerebellar dentate nuclei in ASD displayed greater coupling to broad neocortical regions, and these nuclei related to cognitive function differently such that greater dentate nuclear volume was associated with greater behavioral impairment in ASD but not in controls. Graph analyses demonstrated that the cerebello-thalamocortical network was more densely and less prolifically interconnected in ASD than in typical development. Taken as a whole, our study reveals a developmental interplay between the cerebellum, thalamus, and neocortex which differs in ASD from neurotypical children. This pattern is consistent with a model of ASD in which early developmental influences of cerebellar output on brain maturation are specifically moderated by cerebello-thalamocortical pathways.

neuroscience↗

Structural and functional vascular dysfunction within brain metastases is linked to pembrolizumab inefficacy

Structurally and functionally aberrant vasculature is a hallmark of tumor angiogenesis and treatment resistance. Given the synergistic link between aberrant tumor vasculature and immunosuppression, we analyzed perfusion MRI for 44 patients with brain metastases (BM) undergoing treatment with pembrolizumab. To date, vascular-immune communication, or the relationship between immune checkpoint inhibitor (ICI) efficacy and vascular architecture, has not been well-characterized in human imaging studies. We found that ICI-responsive BM possessed a structurally balanced vascular makeup, which was linked to improved vascular efficiency and an immune-stimulatory microenvironment. In contrast, ICI-resistant BM were characterized by a lack of immune cell infiltration and a highly aberrant vasculature dominated by large-caliber vessels. Peri-tumor region analysis revealed early functional changes predictive of ICI resistance before radiographic evidence on conventional MRI. This study was one of the largest functional imaging studies for BM and establishes a foundation for functional studies that illuminate the mechanisms linking patterns of vascular architecture with immunosuppression, as targeting these aspects of cancer biology may serve as the basis for future combination treatments.

cancer biology↗

Assessing the impact of binary land cover variables on species distribution models: A North Americanstudy on water birds

AimSpecies distribution models (SDMs) are an important tool for predicting species occurrences in geographic space and for understanding the drivers of these occurrences. An effect of environmental variable selection on SDM outcomes has been noted, but how the treatment of variables influences models, including model performance and predicted range area, remains largely unclear. For example, although landcover variables included in SDMs in the form of proportions, or relative cover, recent findings suggest that for species associated with uncommon habitats the simple presence or absence of a landcover feature is most informative. Here we investigate the generality of this hypothesis and determine which representation of environmental features produces the best-performing models and how this affects range area estimates. Finally, we document how outcomes are modulated by spatial grain size, which is known to influence model performance and estimated range area. LocationNorth America MethodsWe fit species distribution models (via Random Forest) for 57 water bird species using proportional and binary estimates of water cover in a grid cell using occurrence data from the eBird citizen science initiative. We evaluated four different thresholds of feature prevalence (land cover representations) within the cell (1%, 10%, 20% or 50%) and fit models across both breeding and non-breeding seasons and multiple grain sizes (1, 5, 10, and 50 km cell lengths). ResultsModel performance was not significantly affected by the type of land cover representation. However, when the models were fitted using binary variables, the model-assessed importance of water bodies significantly decreased, especially at coarse grain sizes. In this binary variable-case, models relied more on other land cover variables, and over-or under-predicted the species range by 5-30%. In some cases, differences up to 70% in predicted species ranges were observed. Main conclusionsMethods for summarizing landcover features are often an afterthought in species distribution modelling. Inaccurate range areas resulting from treatment of landcover features as binary or proportional could lead to the prioritization of conservation efforts in areas where the species do not occur or cause the importance of crucial habitats to be missed. Importantly, our results suggest that at finer grain sizes, binary variables might be more useful for accurately measuring species distributions. For studies using relatively coarse grain sizes, we recommend fitting models with proportional land cover variables.

ecology↗

Spatial and seasonal variation in thermal sensitivity within North American bird species

Responses of wildlife to climate change are typically quantified at the species level, but physiological evidence suggests significant intraspecific variation in thermal sensitivity (non-stationarity) given adaptation to local and seasonal environments. Non-stationarity carries important implications for climate change vulnerability; for instance, sensitivity to extreme weather may increase in specific regions or seasons. Here, we leverage high-resolution observational data from eBird to understand regional and seasonal variation in thermal sensitivity for 20 bird species. Across their ranges, most birds demonstrated spatial and seasonal variation in both thermal optimum and breadth, or the temperature and range of temperatures of peak occurrence. Some birds demonstrated constant thermal optima or breadths (stationarity) while others varied according to local and current environmental conditions (non-stationarity). Across species, birds typically invested in either geographic or seasonal adaptation to climate. Intraspecific variation in thermal sensitivity is likely an important but neglected aspect of organismal responses to climate change.

ecology↗

Abnormal weather drives disease outbreaks in wild and agricultural plants

Predicting effects of climate change on plant disease is critical for protecting ecosystems and food production. Climate change could exacerbate plant disease because parasites may be quicker to acclimate and adapt to novel climatic conditions than their hosts due to their smaller body sizes and faster generation times. Here we show how disease pressure responds to the anomalous weather that will increasingly occur with climate change by compiling a global database (5380 plant populations; 437 unique plant-disease combinations; 2,858,795 individual plant-disease samples) of disease incidence in both agricultural and wild plant systems. Because wild plant populations are assumed to be adapted to local climates, we hypothesized that large deviations from historical conditions would increase disease incidence. By contrast, since agricultural plants have been transported globally, we did not expect the historical climate where they are currently grown to be as predictive of disease incidence. Supporting these hypotheses, we found that disease outbreaks tended to occur during periods of warm temperatures in agricultural and cool-climate wild plant systems, but also occurred in warm-adapted wild (but not agricultural) plant systems experiencing anomalously cool weather. Outbreaks were additionally associated with higher rainfall in wild systems, especially those with historically wet climates. Our results suggest that historical climate affects susceptibility to disease for wild plant-disease systems, while warming drives risks for agricultural plant disease outbreaks regardless of historical climate.

ecology↗

Short- and long-term effects of continuous compost amendment on soil microbiome community

Organic amendment, and especially the use of composts, is a well-accepted sustainable agricultural practice. Compost increases soil carbon and microbial biomass, changes enzymatic activity, and enriches soil carbon and nitrogen stocks. However, relatively little is known about the immediate and long-term temporal dynamics of agricultural soil microbial communities following repeated compost applications. Our study was conducted at two field sites: Newe Yaar (NY, Mediterranean climate) and Gilat (G, semi-arid climate), both managed organically over 4 years under either conventional fertilization (0, zero compost) or three levels of compost amendment (20, 40 and 60 m3/ha or 2, 4, 6 L/m2). Microbial community dynamics in the soils was examined by high-and low-time-resolution analyses. Annual community composition in compost-amended soils was significantly affected by compost amendment levels in G (first, second and third years) and in NY (third year). Repeated sampling at high resolution (9-10 times over 1 year) showed that at both sites, compost application initially induced a strong shift in microbial communities, lasting for up to 1 month, followed by a milder response. Compost application significantly elevated alpha diversity at both sites, but differed in the compost-dose correlation effect. We demonstrate higher abundance of taxa putatively involved in organic decomposition and characterized compost-related indicator taxa and a compost-derived core microbiome at both sites. Overall, this study describes temporal changes in the ecology of soil microbiomes in response to compost vs. conventional fertilization. HighlightsO_LIDose-dependent changes in soil microbiome structure by manure compost application C_LIO_LIDynamic short-and long-term changes in soil microbiomes by compost amendment C_LIO_LIClimate, soil properties and management influence compost-amendment effects C_LIO_LIImmediate and temporal cumulative effects of compost on soil and {beta} diversity C_LI

microbiology↗

Having "multiple selves" helps learning agents explore and adapt in complex changing worlds

Satisfying a variety of conflicting needs in a changing environment is a fundamental challenge for any adaptive agent. Here, we show that designing an agent in a modular fashion as a collection of subagents, each dedicated to a separate need, powerfully enhanced the agents capacity to satisfy its overall needs. We used the formalism of deep reinforcement learning to investigate a biologically relevant multi-objective task: continually maintaining homeostasis of a set of physiologic variables. We then conducted simulations in a variety of environments and compared how modular agents performed relative to standard monolithic agents (i.e., agents that aimed to satisfy all needs in an integrated manner using a single aggregate measure of success). Simulations revealed that modular agents: a) exhibited a form of exploration that was intrinsic and emergent rather than extrinsically imposed; b) were robust to changes in non-stationary environments, and c) scaled gracefully in their ability to maintain home-ostasis as the number of conflicting objectives increased. Supporting analysis suggested that the robustness to changing environments and increasing numbers of needs were due to intrinsic exploration and efficiency of representation afforded by the modular architecture. These results suggest that the normative principles by which agents have adapted to complex changing environments may also explain why humans have long been described as consisting of multiple selves. Significance StatementAdaptive agents must continually satisfy a range of distinct and possibly conflicting needs. In most models of learning, a monolithic agent tries to maximize one value that measures how well it balances its needs. However, this task is difficult when the world is changing and needs are many. Here, we considered an agent as a collection of modules each dedicated to a particular need and competing for control of action. Compared to the standard monolithic approach, modular agents were much better at maintaining homeostasis of a set of internal variables in simulated environments, both static and changing. These results suggest that having multiple selves may represent an evolved solution to the universal problem of balancing multiple needs in changing environments.

neuroscience↗

Circuit dissection and functional validation of a cross-species emotional biomarker

Emotional responses arise from limbic circuits including the hippocampus and amygdala. In the human brain, beta-frequency communication between these structures correlates with self-reported mood and anxiety. However, both the mechanism and significance of this biomarker as a readout vs. driver of emotional state remain unknown. Here we show that beta-frequency communication between the ventral hippocampus and basolateral amygdala also predicts anxiety-related behavior in mice on both long timescales ([~]30 min) and immediately preceding behavioral choices. Genetically encoded voltage indicators reveal that this biomarker reflects synchronization between somatostatin interneurons across both structures. Indeed, synchrony between these neurons dynamically predicts approach vs. avoidance, and optogenetically shifting this synchronization by just 25 msec is sufficient to bidirectionally modulate anxiety-related behaviors. Thus, back-translation establishes a human biomarker as a causal determinant (not just predictor) of emotional state, revealing a novel mechanism whereby interregional synchronization that is frequency-, phase- and cell type-specific controls anxiety processing.

neuroscience↗

Diverse strategies for tracking seasonal environmental niches at hemispheric scale

Species depend upon a constrained set of environmental conditions, or niches, for survival and reproduction that are increasingly lost under climatic change. Seasonal environments require species to either track their niches via movement or undergo physiological or behavioral changes to survive. Here we identify the tracking of both environmental niche position and breadth across 619 New World bird species and assess their phylogenetic and functional underpinning. Partitioning niche position and breadth tracking can inform whether climatic means or extremes limit seasonal distributions. We uncover diverse strategies, including the tracking of niche position, breadth, both, or neither, suggesting highly variable sensitivity to ongoing climatic change. There was limited phylogenetic determinism to this variation, but a strong association with functional attributes that differed between niche position and breadth tracking. Our findings imply significant functional consequences for communities and ecosystems as impending climate change affects some niche tracking strategies more than others.

ecology↗

A bivalent EBV vaccine induces neutralizing antibodies that block B and epithelial cell infection and confer immunity in humanized mice

Epstein Barr virus (EBV) is the major cause of infectious mononucleosis and is associated with several human cancers. Despite its prevalence and major impact on human health, there are currently no specific vaccines or treatments. Four viral glycoproteins, gp 350 and gH/gL/gp42 mediate entry into the major sites of viral replication, B cells and epithelial cells. Here, we designed a nanoparticle vaccine displaying these proteins and show that it elicits potent neutralizing antibodies that protect against infection in vivo. Based on structural analyses, we designed single chain gH/gL and gH/gL/gp42 proteins that were each fused to bacterial ferritin to form a self-assembling nanoparticles. X-ray crystallographic analysis revealed that single chain gH/gL and gH/gL/gp42 adopted a similar conformation to the wild type proteins, and the protein spikes were observed by electron microscopy. Single chain gH/gL or gH/gL/gp42 nanoparticle vaccines were constructed to ensure product homogeneity needed for clinical development. These vaccines elicited neutralizing antibodies in mice, ferrets, and non-human primates that inhibited EBV entry into both B cells and epithelial cells. When mixed with a previously reported gp350 nanoparticle vaccine, gp350D123, no immune competition was observed. To confirm its efficacy in vivo, humanized mice were challenged with EBV after passive transfer of IgG from mice vaccinated with control, gH/gL/gp42+gp350D123 or gH/gL+gp350D123 nanoparticles. While all control animals (6/6) were infected, only one mouse in each vaccine group that received immune IgG had transient low level viremia (1/6). Furthermore, no EBV lymphomas were detected in immune animals in contrast to non-immune controls. This bivalent EBV nanoparticle vaccine represents a promising candidate to prevent EBV infection and EBV-related malignancies in humans. One sentence summaryA bivalent gp350 and gH/gL/gp42 nanoparticle vaccine elicits neutralizing antibodies that protect against EBV infection and EBV lymphoma in vivo.

immunology↗

Genotype-phenotype correlation analysis and therapeutic development using a patient stem cell-derived disease model of Wolfram syndrome

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant which is highly prevalent in the Ashkenazi-Jewish population. Clinical investigation indicates that subjects carrying the homozygous WFS1 c.1672C>T, p.R558C variant show mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C is more stable compared to the other known recessive pathogenic variants associated with Wolfram syndrome. Stem cell-derived islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulates genotype-related Wolfram phenotypes, which are milder than those of SC-islets with compound heterozygous WFS1 c.1672C>T (p.R558C), c.2654C>T (p.P885L). Enhancing residual WFS1 function by a combination treatment of chemical chaperones, sodium 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA), mitigates detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and restored SC-islet function. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient stem cell-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome. One sentence summaryDevelopment of personalized therapy for Wolfram syndrome using genetics and iPSC model.

genetics↗

A Discrete Formulation of Two Alternative Forced Choice Decision Dynamics Derived from a Double-Well Quantum Landscape

Tools from quantum theory have been effectively leveraged in modeling otherwise poorly understood effects in decision-making such as apparent fallacies in probability judgments and context effects. This approach has described the dynamics of two alternative forced choice (2AFC) decisions in terms of the path of a single quantum particle evolving in a single potential well. Here, we present a variant on that approach, which we name the Multi-Particle and Multi-Well (MPMW) quantum cognitive framework, in which decisions among N alternatives are treated by the sum of positional measurements of many independent quantum particles representing stimulus information, acted on by an N-well landscape that defines the decision alternatives. In this article, we apply the MPMW model to the simplest and most common case of N-alternative decision making, 2AFC dynamics. This application calls for a multi-particle double-well implementation, which allows us to construct a simple, analytically tractable discrete drift diffusion model (DDM), in the form of a Markov chain, wherein the parameters of the attractor wells reflect bottom-up (automatic) and top-down (control-dependent) influences on the integration of external information. We first analyze this Markov chain in its simplest form, as a single integrator with a generative process arising from a static quantum landscape and fixed thresholds, and then consider the case of multi-integrator processing under the same conditions. Within this system, stochasticity arises directly from the double-well quantum attractor landscape as a function of the dimensions of its wells, rather than as an external parameter requiring independent fitting. The simplicity of the Markov chain component of this model allows for easy analytical computation of closed forms for response time distributions and response probabilities that match qualitative properties of the accuracies and reaction times of humans performing 2AFC tasks. The MPMW framework produces response time distributions following inverse gaussian curves familiar from previous DDM models and empirical data, including the common observation that mean response times are faster for incorrect than for correct responses. The work presented in this paper serves as a proof of concept, based on which the MPMW framework can be extended to address more complex decision-making processes, (e.g., N-alternative forced choice, dynamic control allocation, and nesting quantum landscapes to allow for modeling at both the task and stimulus levels of processing) that we discuss as future directions.

animal behavior and cognition↗

Baricitinib treatment resolves lower airway inflammation and neutrophil recruitment in SARS-CoV-2-infected rhesus macaques

Effective therapeutics aimed at mitigating COVID-19 symptoms are urgently needed. SARS-CoV-2 induced hypercytokinemia and systemic inflammation are associated with disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor with potent anti-inflammatory properties is currently being investigated in COVID-19 human clinical trials. Recent reports suggest that baricitinib may also have antiviral activity in limiting viral endocytosis. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type I IFN antiviral responses and SARS-CoV-2 specific T cell responses remained similar between the two groups. Importantly, however, animals treated with baricitinib showed reduced immune activation, decreased infiltration of neutrophils into the lung, reduced NETosis activity, and more limited lung pathology. Moreover, baricitinib treated animals had a rapid and remarkably potent suppression of alveolar macrophage derived production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for severe inflammation induced by SARS-CoV-2 infection.

immunology↗

Transient cell-in-cell formation underlies tumor resistance to immunotherapy

Despite the remarkable success of immunotherapy in cancer, most patients will develop resistant tumors. While the main conceptual paradigm suggests that relapsed clones emerge through a process of clonal selection and immunoediting, currently little evidence directly demonstrates this process in epithelial cancers. To study this process, we established several mouse models in which tumors drastically regress following immunotherapy, yet resistant tumors relapse within a few weeks of treatment cessation. Whole exome analyses indicated that relapsed tumors share hundreds of neo-antigens with the primary tumors and are comparably killed by reactive T cells. Examination of tumor cells that survive immunotherapies revealed that they structure a transient cell-in-cell formation, which is impenetrable to immune-derived cytotoxic compounds and to chemotherapies. This formation is mediated predominantly by a cell-membrane protein on activated T cells, which subsequently induces epidermal growth factor receptors and STAT3 phosphorylation in tumors cells. In contrast to previous reports on cell-in-cell formations, here both cells remain alive and can disseminate into single tumor cells once T cells are no longer present. Overall, this work highlights a powerful resistance mechanism which enable tumor cells to survive immune pressure and provides a new theoretical framework for combining chemotherapies and immunotherapies.

immunology↗

Extracellular ATP released from Candida albicans activates non-peptidergic neurons to augment host defense

Intestinal microbes release ATP to modulate local immune responses. Herein we demonstrates that Candida albicans, an opportunistic commensal fungus, also modulates immune responses via secretion of ATP. We found that ATP secretion from C. albicans varied between standard laboratory strains. A survey of eighty-nine clinical isolates revealed heterogeneity in ATP secretion, independent of growth kinetics and intracellular ATP levels. Isolates from blood released less ATP than commensals, suggesting that ATP secretion assists with commensalism. To confirm this, cohorts of mice were infected with strains matched for origin, and intracellular ATP concentration, but high or low extracellular ATP. In all cases fungal burden was inversely correlated with ATP secretion. Mice lacking P2RX7, the key ATP receptor expressed by immune cells in the skin, showed no alteration in fungal burden. Rather, treatments with a P2RX2/3 antagonist result in increased fungal burden. P2RX2/3 is expressed by non-peptidergic neurons that terminate in the epidermis. Cultured sensory neurons flux Ca2+ when exposed to supernatant from heat-killed C. albicans (HKCA), and these non-peptidergic fibers are the dominant subset that respond to HKCA. Ca2+ flux, but not CGRP-release, can be abrogated by pretreatment of HKCA supernatant with apyrase. To determine whether non-peptidergic neurons participate in host defense, we generated MRGPRD-DTR mice. Infection in these mice resulted in increased CFU only for those C. albicans strains with high ATP secretion. Taken together, our findings indicate that C. albicans releases ATP, which is recognized by non-peptidergic nerves in the skin resulting in augmented anti-Candida immune responses. Author SummaryBacterial release of ATP has been shown to modulate immune responses. Candida albicans displays heterogeneity in ATP release among laboratory strains and commensal clinical isolates release more ATP than invasive isolates. C. albicans strains with high ATP secretion show lower fungal burden following epicutaneous infection. Mice lacking P2RX7, the key ATP receptor expressed by immune cells, showed no alteration in fungal burden. In contrast, treatment with P2RX2/3 antagonists resulted in increased fungal burden. P2RX3 is expressed by a subset of non-peptidergic neurons that terminate in the epidermis. These non-peptidergic fibers are the predominant responders when cultured sensory neurons are exposed to heat-killed C. albicans in vitro. Mice lacking non-peptidergic neurons have increased infection when exposed to high but not low ATP-secreting isolates of C. albicans. Taken together, our findings indicate that C. albicans releases ATP which is recognized by non-peptidergic nerves in the skin resulting in augmented anti-Candida immune responses. Bullet pointsO_LIATP released from heat killed C. albicans activates non-peptidergic sensory neurons C_LIO_LILive C. albicans clinical isolates release variable amounts of ATP C_LIO_LIElevated levels of ATP released by C. albicans correlates with reduced infectivity in vivo C_LIO_LIMRGPRD-expressing cutaneous neurons are required for defense against ATP-secreting C. albicans C_LI

immunology↗

Long-term alterations in brain and behavior after postnatal Zika virus infections in infant macaques

Considering the impact that Zika virus (ZIKV) infection has on the fetal nervous system and given that the postnatal period is also a time of rapid brain growth, it is important to understand the potential neurobehavioral consequences of ZIKV infection during infancy. Postnatal ZIKV infection in a rhesus macaque (RM) model resulted in long-term behavioral, motor, and cognitive changes, including increased emotional reactivity, decreased social contact, loss of balance, and deficits in visual recognition memory at one year of age. Structural and functional MRI showed that ZIKV-infected infant RMs had persistent enlargement of lateral ventricles, smaller volumes and altered functional connectivity between brain areas important for socioemotional behavior, cognitive, and motor function (e.g. amygdala, hippocampus, cerebellum). Neuropathological changes corresponded with neuroimaging results and were consistent with the behavioral and memory deficits. Overall, this study demonstrates that postnatal ZIKV infection of infants in this model has long lasting neurodevelopmental consequences.

neuroscience↗