Zinc and manganese chelation by neutrophil S100A8/A9 (Calprotectin) limits extracellular aspergillus fumigatus hyphal growth and corneal infection

PMCID: PMC4684987.-- et al.Calprotectin, a heterodimer of S100A8 and S100A9, is an abundant neutrophil protein that possesses antimicrobial activity primarily because of its ability to chelate zinc and manganese. In the current study, we showed that neutrophils from calprotectindeficient S100A9 mice have an impaired ability to inhibit Aspergillus fumigatus hyphal growth in vitro and in infected corneas in a murine model of fungal keratitis; however, the ability to inhibit hyphal growth was restored in S100A9 mice by injecting recombinant calprotectin. Furthermore, using recombinant calprotectin with mutations in either the Zn and Mn binding sites or the Mn binding site alone, we show that both zinc and manganese binding are necessary for calprotectin's antihyphal activity. In contrast to hyphæ, we found no role for neutrophil calprotectin in uptake or killing of intracellular A. fumigatus conidia either in vitro or in a murine model of pulmonary aspergillosis. We also found that an A. fumigatus δzafA mutant, which demonstrates deficient zinc transport, exhibits impaired growth in infected corneas and following incubation with neutrophils or calprotectin in vitro as compared with wild-type. Collectively, these studies demonstrate a novel stage-specific susceptibility of A. fumigatus to zinc and manganese chelation by neutrophil-derived calprotectin.This work was supported by National Eye Institute Grant R01 EY18612 (to E.P.), Visual Science Research Center Core Grant P30EY011373 (to Case Western Reserve University), National Institute of Allergy and Infectious Diseases Grant R01 AI101171 (to E.P.S. and W.J.C.), National Institute of Allergy and Infectious Diseases Immunology Training Grant 5T32AI089474 (to H.L.C.), National Eye Institute Visual Science Training Grant T32 EY007157 (to H.L.C.), and National Eye Institute National Research Service Award Grant 1F30EY025548-01 (to H.L.C.). T.M.H. and A.J. received Lucille Castori Center for Microbes, Inflammation, and Cancer Grants and National Institute of Allergy and Infectious Diseases Grants R01 AI093808 and R21 AI105617 (to T.M.H.). T.M.H. is an investigator in the Pathogenesis of Infectious Diseases supported by the Burroughs Wellcome Fund. J.A.C. was supported by the Spanish Ministry of Economy and Competitiveness through Grant SAF2013-48382-R.Peer Reviewe

Applying OGC sensor web enablement to ocean observing systems

The complexity of marine installations for ocean observing systems has grown significantly in recent years. In a network consisting of tens, hundreds or thousands of marine instruments, manual configuration and integration becomes very challenging. Simplifying the integration process in existing or newly established observing systems would benefit system operators and is important for the broader application of different sensors. This article presents an approach for the automatic configuration and integration of sensors into an interoperable Sensor Web infrastructure. First, the sensor communication model, based on OGC's SensorML standard, is utilized. It serves as a generic driver mechanism since it enables the declarative and detailed description of a sensor's protocol. Finally, we present a data acquisition architecture based on the OGC PUCK protocol that enables storage and retrieval of the SensorML document from the sensor itself, and automatic integration of sensors into an interoperable Sensor Web infrastructure. Our approach adopts Efficient XML Interchange (EXI) as alternative serialization form of XML or JSON. It solves the bandwidth problem of XML and JSON.Peer ReviewedPostprint (author's final draft

Next generation of web enabled ocean sensor systems

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Interoperability developments for next generation multifunctional ocean sensor systems in nexos

Peer Reviewe

Efficacy of Galcanezumab for Migraine Prevention in Patients With a Medical History of Anxiety and/or Depression: A Post Hoc Analysis of the Phase 3, Randomized, Double-Blind, Placebo-Controlled REGAIN, and Pooled EVOLVE-1 and EVOLVE-2 Studies

© 2020 Eli Lilly and Company. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC, on behalf of American Headache Society Objective: This post hoc analysis evaluated the efficacy of galcanezumab for the prevention of migraine in patients with and without comorbid anxiety and/or depression. Background: Patients with migraine have a higher risk of anxiety and/or depression. Given the high prevalence of psychiatric symptoms and their potential negative prognostic impact, determining the efficacy of migraine treatments in patients with these comorbidities is important. Methods: The results of 2 phase 3 episodic migraine studies of patients with 4-14 migraine headache days (MHD) per month were pooled. A third chronic migraine study, which was evaluated separately, enrolled patients with ≥15 headache days per month, of which ≥8 had migraine-like features. Patients in all 3 studies were randomized 2:1:1 to placebo, galcanezumab 120 mg, or galcanezumab 240 mg. The efficacy of galcanezumab on migraine was measured in subgroups of patients with anxiety and/or depression (current or past) and patients without. A repeated measures model was used to compare treatment groups within each subgroup and to test for consistency of treatment effect across the anxiety/depression subgroups (subgroup-by-treatment interaction) during the double-blind treatment phases. Results: Among 1773 intent-to-treat patients with episodic migraine, both doses of galcanezumab demonstrated statistically significant improvements relative to placebo in overall number of MHD for the subgroups of patients with anxiety and/or depression (mean change difference from placebo [95% CI]: −2.07 [−2.81, −1.33] for galcanezumab 120 mg [P \u3c.001], −1.91 [−2.78, −1.04] for 240 mg [P \u3c.001]) and without anxiety and/or depression (mean change difference from placebo [95% CI]: −1.92 [−2.36, −1.47] for 120 mg [P \u3c.001], −1.77 [−2.20, −1.33] for 240 mg [P \u3c.001]), as was observed for the secondary outcomes of MHD with acute medication use and functional impairment. Among 1113 intent-to-treat patients with chronic migraine, those with anxiety and/or depression had significant reductions in overall MHD frequency with the 240-mg dose (mean change difference from placebo [95% CI]: −1.92 [−3.52, −0.33]; P =.018), whereas significant reductions were observed at both the 120-mg (mean change difference from placebo [95% CI]: −2.29 [−3.26, −1.31]; P \u3c.001) and 240-mg (−1.85 [−2.83, −0.87]; P \u3c.001) doses in patients without anxiety and/or depressions. Significant reductions (P \u3c.01) in MHD with acute medication use were observed at both doses within both anxiety/depression subgroups and for overall functional impairment for patients without anxiety and/or depression, though neither dose significantly reduced overall functional impairment beyond placebo in the subgroup with anxiety and/or depression. In the episodic and chronic migraine studies, the subgroup-by-treatment interaction was not statistically significant for MHD, MHD with acute medication use, or functional impairment (chronic study only), suggesting a lack of evidence of differential effect between subgroups. Furthermore, differences between subgroups in the mean change differences from placebo, as well as overlapping 95% confidence intervals for the subgroups, indicated lack of a clinical or statistical difference between subgroups for these outcome variables. There was a significantly higher percentage of patients with episodic migraine attaining ≥50%, ≥75%, and 100% reductions, and a higher percentage of patients with chronic migraine attaining ≥50% and ≥75% reductions from baseline with galcanezumab compared with placebo, regardless of medical history of anxiety and/or depression. Conclusions: A medical history of anxiety and/or depression does not seem to interfere with response to galcanezumab among patients with episodic migraine, and both doses of galcanezumab appear efficacious for these individuals regardless of this psychiatric history. Among patients with chronic migraine and comorbid anxiety and/or depression, the 240-mg dose, but not the 120-mg dose, significantly decreased overall MHD, but neither dose resulted in significantly greater functional improvement. Patients with migraine and comorbid anxiety and/or depression often require additional interventions, and this may be more important in chronic migraine

Interoperability developments for next generation multifunctional ocean sensor systems in NeXOS

Sensor technology is rapidly advancing, enabling smaller and less expensive instruments to monitor Earth’s environment. It is expected that many more kinds and quantities of networked environmental sensors will be deployed in coming years. This work presents an approach for the smart configuration and integration of marine sensors into an interoperable Sensor Web infrastructure such that the overall life cycle cost of sensors and observing systems is reduced and data has greater societal and scientific value. In this paper some of the objectives related to sensor interface included in the project proposal NeXOS (Next generation, Cost-effective, Compact, Multifunctional Web Enabled Ocean Sensor Systems Empowering Marine, Maritime and Fisheries Management), under the European Commission’s Ocean of Tomorrow call FP7- OCEAN-2013.2, are presented.Peer ReviewedPostprint (published version

Procedures to Improve Sensor Data Quality

The oceans play an important role in aspects of global sustainability, including climate change, food security and human health. Because of its vast dimensions, internal complexity, and limited accessibility, efficient monitoring and predicting of the ocean forms a collaborative effort of regional and global scale. A key requirement for ocean observing is the need to follow well-defined approaches. Summarized under “Ocean Best Practices” (OBP) are all aspects of ocean observing that require proper and agreed-on documentation, from manuals and standard operating procedures for sensors, strategies for structuring observing systems and associated products, to ethical and governance aspects when executing ocean observing. In Task 6.2 we have developed new tools, and organized workshops with outcomes of Best Practice manuals and scientific publications. The focus has been on improving accuracy of trace element measurements in seawater and also of marine omics analysis, and enhancing reliability, interoperability and quality of sensor measurements for dissolved oxygen, nutrients and carbonate chemistry measurements

NeXOS A1: Smart hydrophone integration into the sensor web enablement framework

The integration of marine sensors systems into marine observation platforms such as gliders, cabled observatories and smart buoys require a great deal of effort due to the lack of standardization and diversity of architectures used in marine technologies. The NeXOS project addresses this issue proposing the adoption of the SEISI architecture (Smart Electronic Interface for Sensor Interoperability). This paper presents a case of use of this architecture, integrating the A1 Hydrophone developed within the NeXOS into a Smart Buoy using the OGC Sensor Web Enablement framework.Postprint (author's final draft