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The innate immune system is critical for host defense against microbial pathogens, yet many pathogens express virulence factors that impair immune function. Here, we used the bacterial pathogenLegionella pneumophilato understand how the immune system successfully overcomes pathogen subversion mechanisms.L. pneumophilareplicates within macrophages by using a type IV secretion system to translocate bacterial effectors into the host cell cytosol. As a consequence of effector delivery, host protein synthesis is blocked at several steps, including translation initiation and elongation. Despite this translation block, infected cells robustly produce proinflammatory cytokines, but the basis for this is poorly understood. By using a reporter system that specifically discriminates between infected and uninfected cells within a population, we demonstrate here that infected macrophages produced IL-1α and IL-1β, but were poor producers of IL-6, TNF, and IL-12, which are critical mediators of host protection. Uninfected bystander cells robustly produced IL-6, TNF, and IL-12, and this bystander response required IL-1 receptor (IL-1R) signaling during early pulmonary infection. Our data demonstrate functional heterogeneity in production of critical protective cytokines and suggest that collaboration between infected and uninfected cells enables the immune system to bypass pathogen-mediated translation inhibition to generate an effective immune response.

The innate immune system is critical for host defense against microbial pathogens, yet many pathogens express virulence factors that impair immune function. Here, we used the bacterial pathogen Legionella pneumophila to understand how the immune system successfully overcomes pathogen subversion mechanisms. L. pneumophila replicates within macrophages by using a type IV secretion system to translocate bacterial effectors into the host cell cytosol. As a consequence of effector delivery, host protein synthesis is blocked at several steps, including translation initiation and elongation. Despite this translation block, infected cells robustly produce proinflammatory cytokines, but the basis for this is poorly understood. By using a reporter system that specifically discriminates between infected and uninfected cells within a population, we demonstrate here that infected macrophages produced IL-1α and IL-1β, but were poor producers of IL-6, TNF, and IL-12, which are critical mediators of host protection. Uninfected bystander cells robustly produced IL-6, TNF, and IL-12, and this bystander response required IL-1 receptor (IL-1R) signaling during early pulmonary infection. Our data demonstrate functional heterogeneity in production of critical protective cytokines and suggest that collaboration between infected and uninfected cells enables the immune system to bypass pathogen-mediated translation inhibition to generate an effective immune response. Significance Pathogens use virulence factors to inhibit key immune cell functions and would be expected to impair immune responses to infection. However, immune responses are still generated against infection, suggesting that the immune system has evolved mechanisms for overcoming pathogenic activity. Here, we demonstrate that cells infected with Legionella pneumophila synthesize IL-1 despite a pathogen-imposed block in host translation, but are unable to produce other critical cytokines. IL-1 signaling allows uninfected bystander cells to produce protective cytokines. Our data thus demonstrate a key role for communication between infected and uninfected bystander cells in overcoming pathogenic activities. This mechanism of immune activation has broad significance for our understanding of how successful immune responses are generated against pathogens.

During the charging and discharging of lithium-ion-battery cathodes through the de- and reintercalation of lithium ions, electroneutrality is maintained by transition-metal redox chemistry, which limits the charge that can be stored. However, for some transition-metal oxides this limit can be broken and oxygen loss and/or oxygen redox reactions have been proposed to explain the phenomenon. We present operando mass spectrometry of 18 O-labelled Li 1.2 [Ni 0.13 2+ Co 0.13 3+ Mn 0.54 4+ ]O 2 , which demonstrates that oxygen is extracted from the lattice on charging a Li 1.2 [Ni 0.13 2+ Co 0.13 3+ Mn 0.54 4+ ]O 2 cathode, although we detected no O 2 evolution. Combined soft X-ray absorption spectroscopy, resonant inelastic X-ray scattering spectroscopy, X-ray absorption near edge structure spectroscopy and Raman spectroscopy demonstrates that, in addition to oxygen loss, Li + removal is charge compensated by the formation of localized electron holes on O atoms coordinated by Mn 4+ and Li + ions, which serve to promote the localization, and not the formation, of true O 2 2− (peroxide, O–O ~1.45 Å) species. The quantity of charge compensated by oxygen removal and by the formation of electron holes on the O atoms is estimated, and for the case described here the latter dominates. The energy that can be stored in lithium-ion batteries is typically limited by the redox chemistry of the transition metals within the cathodes. Now it is shown that for Li 1.2 [Ni 2+ 0.13 Co 3+ 0.13 Mn 4+ 0.54 ]O 2 , a 3 d -transition-metal oxide that breaks this limit, Li-ion extraction is charge compensated not just by transition-metal oxidation but also through the generation of localized electron-holes on oxygen.

In this randomized trial of deep-brain stimulation targeted to either the globus pallidus interna or the subthalamic nucleus in patients with advanced Parkinson's disease, the patients assigned to pallidal stimulation and those assigned to subthalamic stimulation had a similar improvement in motor function. In this trial of deep-brain stimulation targeted to either the globus pallidus interna or the subthalamic nucleus in patients with advanced Parkinson's disease, the patients assigned to pallidal stimulation and those assigned to subthalamic stimulation had a similar improvement in motor function. Randomized studies have shown that treatment with deep-brain stimulation, which involves the surgical implantation of a device that sends electrical impulses to specific parts of the brain, is superior to medical therapy for improving motor function and quality of life for patients with advanced Parkinson's disease. 1 , 2 The globus pallidus interna and the subthalamic nucleus are both accepted targets for deep-brain stimulation. The subthalamic nucleus is used more commonly as the target, despite the lack of evidence showing that neurostimulation of this target provides a better outcome. Our multicenter, randomized, blinded trial, called the Veterans Affairs Cooperative Studies Program (CSP) . . .

Tracking changes in seabird populations from remote Arctic regions using traditional monitoring techniques is financially and logistically challenging, leading to limited information on historical population trends. In this pilot study, we use a novel application of paleolimnological proxies to track environmental change using bird nests. Specifically, we examine long-term population dynamics of the Northern Common Eider ( Somateria mollissima borealis ), a philopatric sea duck. Eider nests from the Canadian sub-Arctic were sampled and radioisotopically dated, indicating that eiders have been nesting here since the 1800s. To assess the applicability of paleoecological proxies in nests to monitor environmental changes and long-term eider population dynamics, we examined changes in diatom species composition, shifts in the abundance of siliceous proxies (i.e., diatoms, chrysophyte cysts, phytoliths, protozoan plates), visible reflectance spectroscopy-inferred chlorophyll a (VRS-chla), stable nitrogen isotopes, and a selection of metal(loid)s. Warmer post-Little Ice Age conditions after the mid-19 th century, together with higher eider occupation rates, promoted the proliferation of diatoms and other siliceous indicators. Declining eider populations during the industrial era, likely due to increased hunting pressures, was indicated by declines in δ 15 N values and relative abundances of diatom taxa typically associated with higher nutrients and/or moisture. Increasing concentrations of metals (i.e., Zn and Cd), δ 15 N values, and VRS-chla, which are positively associated with eider nesting activity, provided further support that eider numbers increased during the latter part of the 20 th century. Our study shows that the accumulated vegetative and peat material from eider nests can provide a powerful tool to track historical bird population dynamics in ways that traditional, more recent, population monitoring methods cannot. Collectively, these methods can contribute insights to guide conservation decisions of this harvested species and other under-surveyed species.

[This corrects the article DOI: 10.1371/journal.pone.0332605.].

The coastal marine ecosystem near the Elwha River was altered by a massive sediment influx-over 10 million tonnes-during the staged three-year removal of two hydropower dams. We used time series of bathymetry, substrate grain size, remotely sensed turbidity, scuba dive surveys, and towed video observations collected before and during dam removal to assess responses of the nearshore subtidal community (3 m to 17 m depth). Biological changes were primarily driven by sediment deposition and elevated suspended sediment concentrations. Macroalgae, predominantly kelp and foliose red algae, were abundant before dam removal with combined cover levels greater than 50%. Where persistent sediment deposits formed, macroalgae decreased greatly or were eliminated. In areas lacking deposition, macroalgae cover decreased inversely to suspended sediment concentration, suggesting impacts from light reduction or scour. Densities of most invertebrate and fish taxa decreased in areas with persistent sediment deposition; however, bivalve densities increased where mud deposited over sand, and flatfish and Pacific sand lance densities increased where sand deposited over gravel. In areas without sediment deposition, most invertebrate and fish taxa were unaffected by increased suspended sediment or the loss of algae cover associated with it; however, densities of tubeworms and flatfish, and primary cover of sessile invertebrates increased suggesting benefits of increased particulate matter or relaxed competition with macroalgae for space. As dam removal neared completion, we saw evidence of macroalgal recovery that likely owed to water column clearing, indicating that long-term recovery from dam removal effects may be starting. Our results are relevant to future dam removal projects in coastal areas and more generally to understanding effects of increased sedimentation on nearshore subtidal benthic communities.

Brain metastases are refractory to therapies that control systemic disease in patients with human epidermal growth factor receptor 2 (HER2+) breast cancer, and the brain microenvironment contributes to this therapy resistance. Nutrient availability can vary across tissues, therefore metabolic adaptations required for brain metastatic breast cancer growth may introduce liabilities that can be exploited for therapy. Here, we assessed how metabolism differs between breast tumors in brain versus extracranial sites and found that fatty acid synthesis is elevated in breast tumors growing in brain. We determine that this phenotype is an adaptation to decreased lipid availability in brain relative to other tissues, resulting in a site-specific dependency on fatty acid synthesis for breast tumors growing at this site. Genetic or pharmacological inhibition of fatty acid synthase (FASN) reduces HER2+ breast tumor growth in the brain, demonstrating that differences in nutrient availability across metastatic sites can result in targetable metabolic dependencies.

Habitat diversity and heterogeneity play a fundamental role in structuring ecological communities. Dam emplacement and removal can fundamentally alter habitat characteristics, which, in turn, can affect associated biological communities. Beginning in the early 1900s, the Elwha and Glines Canyon dams in Washington, USA, withheld an estimated 30 million Mg of sediment from river, coastal, and nearshore habitats. During the staged removal of these dams, the largest dam removal project in history, over 14 million Mg of sediment were released from the former reservoirs. Our interdisciplinary study in coastal habitats, the first of its kind, shows how the physical changes to the river delta and estuary habitats during dam removal were linked to responses in biological communities. Sediment released during dam removal resulted in over a meter of sedimentation in the estuary and over 400 m of expansion of the river mouth delta landform. These changes increased the amount of supratidal and intertidal habitat, but also reduced the influx of seawater into the pre-removal estuary complex. The effects of these geomorphic and hydrologic changes cascaded to biological systems, reducing the abundance of macroinvertebrates and fish in the estuary and shifting community composition from brackish to freshwater-dominated species. Vegetation did not significantly change on the delta, but pioneer vegetation increased during dam removal, coinciding with the addition of newly available habitat. Understanding how coastal habitats respond to large-scale human stressors, and in some cases the removal of those stressors, is increasingly important as human uses and restoration activities increase in these habitats.

Algal bioindicators, such as diatoms, often show subdued responses to eutrophication in Arctic lakes because climate‐related changes (e.g., ice cover) tend to be the overriding factors influencing assemblage composition. Here, we examined how sub‐Arctic ponds historically receiving high nutrient inputs from nesting seabirds have responded to recent climate change. We present diatom data obtained from 12 sediment cores in seaduck‐affected ponds located on islands through Hudson Strait, Canada. All study cores show consistently elevated values of sedimentary ẟ15N, an established proxy for tracking marine‐derived nutrients, indicating seabirds have been present on these islands for at least the duration of the sediment records (~100 to 400 years). We document diverse epiphytic diatom assemblages to the base of all sediment cores, which is in marked contrast to seabird‐free Arctic ponds—these oligotrophic sites typically record epilithic diatom flora prior to recent warming. Diatoms are likely responding indirectly to seabird nutrients via habitat as nutrients promote the growth of mosses supporting epiphytic diatom communities. This masks the typical diatom response to increased warming in the Arctic, which also results in habitat changes and the growth of mosses around the pond edges. Changes in sedimentary chlorophyll a were not consistently synchronous with large changes in ẟ15N values, suggesting that primary production in ponds is not responding linearly to changes in seabird‐derived nitrogen. Across all ponds, we recorded shifts in diatom epiphytic assemblages (e.g., increases in % relative abundance of many Nitzschia species) that often align with increases in chlorophyll a. The changes in diatoms and chlorophyll a, although variable, are most likely driven by climate change as they are generally consistent with longer ice‐free conditions and growing seasons. Together, our results show that to effectively use diatoms in animal population reconstructions across the sub‐Arctic and Arctic, a strong understanding of eutrophication and climate change, based on supplementary proxies, is also required. We document diverse epiphytic diatom assemblages to the base of all sediment cores, which is in marked contrast to seabird‐free Arctic ponds—these oligotrophic sites typically record epilithic diatom flora prior to recent warming. Diatoms are likely responding indirectly to seabird nutrients via habitat as nutrients promote the growth of mosses supporting epiphytic diatom communities. Changes in sedimentary chlorophyll a were not consistently synchronous with large changes in ẟ15N values, suggesting that primary production in ponds is not responding linearly to changes in seabird‐derived nitrogen.