Background and Purpose
H2O2 is widely understood to regulate intracellular signalling. In airway epithelia, H2O2 stimulates anion secretion primarily by activating an autocrine PGE2 signalling ...pathway via EP4 and EP1 receptors to initiate cytic fibrosis transmembrane regulator (CFTR)‐mediated Cl− secretion. This study investigated signalling downstream of the receptors activated by H2O2.
Experimental Approach
Anion secretion by differentiated bronchial epithelial cells was measured in Ussing chambers during stimulation with H2O2, an EP4 receptor agonist or β2‐adrenoceptor agonist in the presence and absence of inhibitors of ACs and downstream effectors. Intracellular calcium (Ca2+I) changes were followed by microscopy using fura–2‐loaded cells and PKA activation followed by FRET microscopy.
Key Results
Transmembrane adenylyl cyclase (tmAC) and soluble AC (sAC) were both necessary for H2O2 and EP4 receptor‐mediated CFTR activation in bronchial epithelia. H2O2 and EP4 receptor agonist stimulated tmAC to increase exchange protein activated by cAMP (Epac) activity that drives PLC activation to raise Ca2+i via Ca2+ store release (and not entry). Increased Ca2+i led to sAC activation and further increases in CFTR activity. Stimulation of sAC did not depend on changes in HCO3−. Ca2+‐activated apical KCa1.1 channels and cAMP‐activated basolateral KV7.1 channels contributed to H2O2‐stimulated anion currents. A similar Epac‐mediated pathway was seen following β2‐adrenoceptor or forskolin stimulation.
Conclusions and Implications
H2O2 initiated a complex signalling cascade that used direct stimulation of tmACs by Gαs followed by Epac‐mediated Ca2+ crosstalk to activate sAC. The Epac‐mediated Ca2+ signal constituted a positive feedback loop that amplified CFTR anion secretion following stimulation of tmAC by a variety of stimuli.
Networked detector systems can be deployed in urban environments to aid in the detection and localization of radiological and/or nuclear material. However, effectively responding to and interpreting ...a radiological alarm using spectroscopic data alone may be hampered by a lack of situational awareness, particularly in complex environments. This study investigates the use of Light Detection and Ranging (LiDAR) and streaming video to enable real-time object detection and tracking, and the fusion of this tracking information with radiological data for the purposes of enhanced situational awareness and increased detection sensitivity. This work presents an object detection, tracking, and novel source-object attribution analysis that is capable of operating in real time. By implementing this analysis pipeline on a custom-developed system that comprises a static 2 in. <inline-formula> <tex-math notation="LaTeX">\times 4 </tex-math></inline-formula> in. <inline-formula> <tex-math notation="LaTeX">\times16 </tex-math></inline-formula> in. NaI(Tl) detector colocated with a 64-beam LiDAR and four monocular cameras, we demonstrate the ability to accurately correlate trajectories from tracked objects to spectroscopic gamma-ray data in real time and use physics-based models to reliably discriminate between source-carrying and nonsource-carrying objects. In this work, we describe our approach in detail and present a quantitative performance assessment that characterizes the source-object attribution capabilities of both video and LiDAR. Additionally, we demonstrate the ability to simultaneously track pedestrians and vehicles in a mock urban environment and use this tracking information to improve both detection sensitivity and situational awareness using our contextual-radiological data fusion methodology.
One of the most prominent hypotheses to explain the ubiquity of sex and recombination is based on host–parasite interactions. Under the name of the Red Queen hypothesis (RQH), it has had theoretical ...and empirical support since its conception, but recent theoretical work has shown that the circumstances under which the RQH works remain unclear. Here we review the current status of the theory of the RQH. We argue that recent theoretical work calls for new experimental data and an increased theoretical effort to reveal the driving force of the RQH.
The ability to formulate maps of minimum detectable activities (MDAs) that describe the sensitivity of an ad hoc measurement that used one or more freely moving radiation detector systems would be ...significantly beneficial for the conduct and understanding of many radiological search activities. In a real-time scenario with a free-moving detector system, an MDA map can provide useful feedback to the operator about which areas have not been searched as thoroughly as others, thereby allowing the operator to prioritize future actions. Similarly, such a calculation could be used to inform subsequent navigation decisions of autonomous platforms. Here we describe a near real-time MDA mapping approach that can be applied when searching for point sources using detected events in a spectral region of interest (ROI) while assuming a constant, unknown background rate. We show the application of this MDA mapping method to a real scenario, a survey of the interior of a small building using a handheld detector system. Repeated measurements with no sources and with 137Cs sources of different strengths yield results consistent with the estimated thresholds and MDA values; namely, that for background-only measurements no sources are seen above threshold anywhere in the scene, while when sources are present they are detected above the thresholds calculated for their locations.
When searching for radiological sources in an urban area, a vehicle-borne detector system will often measure complex, varying backgrounds primarily from natural gamma-ray sources. Much work has been ...focused on developing spectral algorithms that retain sensitivity and minimize the false-positive rate even in the presence of such spectral and temporal variability. However, information about the environment surrounding the detector system might also provide useful clues about the expected background, which if incorporated into an algorithm, could improve performance. Recent work has focused on extensive measuring and modeling of urban areas with the goal of understanding how these complex backgrounds arise. This work presents an analysis of panoramic video images and gamma-ray background data collected in Oakland, California, by the radiological multisensor analysis platform (RadMAP) vehicle. Features were extracted from the panoramic images by semantically labeling the images and then convolving the labeled regions with the detector response. A linear model was used to relate the image-derived features to gamma-ray spectral features obtained using nonnegative matrix factorization (NMF) under different regularizations. We find some gamma-ray background features correlate strongly with image-derived features that measure the response-adjusted solid angle subtended by sky and buildings, and we discuss the implications for the development of future, contextually aware detection algorithms.
► New methodology for supernova detection with IceCube. ► New observables granting access to neutrino emission spectrum. ► IceCube extension for routine supernova detection.
The current supernova ...detection technique used in IceCube relies on the sudden deviation of the summed photomultiplier noise rate from its nominal value during the neutrino burst, making IceCube a ≈3 Megaton effective detection volume – class supernova detector. While galactic supernovae can be resolved with this technique, the supernova neutrino emission spectrum remains unconstrained and thus presents a limited potential for the topics related to supernova core collapse models.
The paper elaborates analytically on the capabilities of IceCube to detect supernovae through the analysis of hits in the detector correlated in space and time. These arise from supernova neutrinos interacting in the instrumented detector volume along single strings. Although the effective detection volume for such coincident hits is much smaller (≳35kton, about the scale of SuperK), a wealth of information is obtained due to the comparatively low rate of coincident noise hits. We demonstrate that a neutrino flux from a core collapse supernova will produce a signature enabling the resolution of rough spectral features and, in the case of a strong signal, providing indication on its location.
We further discuss the enhanced potential of a rather modest detector extension, a denser array in the center of IceCube, within our one dimensional analytic calculation framework. Such an extension would enable the exploration of the neutrino sky above a few GeV and the detection of supernovae up to a few 100’s of kilo parsec. However, a 3–4Mpc detection distance, necessary for routine supernova detection, demands a significant increase of the effective detection volume and can be obtained only with a more ambitious instrument, particularly the boosting of sensor parameters such as the quantum efficiency and light collection area.
Digital contact tracing is a relevant tool to control infectious disease outbreaks, including the COVID-19 epidemic. Early work evaluating digital contact tracing omitted important features and ...heterogeneities of real-world contact patterns influencing contagion dynamics. We fill this gap with a modeling framework informed by empirical high-resolution contact data to analyze the impact of digital contact tracing in the COVID-19 pandemic. We investigate how well contact tracing apps, coupled with the quarantine of identified contacts, can mitigate the spread in real environments. We find that restrictive policies are more effective in containing the epidemic but come at the cost of unnecessary large-scale quarantines. Policy evaluation through their efficiency and cost results in optimized solutions which only consider contacts longer than 15-20 minutes and closer than 2-3 meters to be at risk. Our results show that isolation and tracing can help control re-emerging outbreaks when some conditions are met: (i) a reduction of the reproductive number through masks and physical distance; (ii) a low-delay isolation of infected individuals; (iii) a high compliance. Finally, we observe the inefficacy of a less privacy-preserving tracing involving second order contacts. Our results may inform digital contact tracing efforts currently being implemented across several countries worldwide.
Protein tyrosine phosphatase 1B (PTP1B) has anti-inflammatory potential but PTP1B responses are desensitized in the lung by prolonged cigarette smoke exposure. Here we investigate whether PTP1B ...expression affects lung disease severity during respiratory syncytial viral (RSV) exacerbations of chronic obstructive pulmonary disease (COPD). Ptp1b(-/-) mice infected with RSV exhibit exaggerated immune cell infiltration, damaged epithelial cell barriers, cytokine production, and increased apoptosis. Elevated expression of S100A9, a damage-associated molecular pattern molecule, was observed in the lungs of Ptp1b(-/-) mice during RSV infection. Utilizing a neutralizing anti-S100A9 IgG antibody, it was determined that extracellular S100A9 signaling significantly affects lung damage during RSV infection. Preexposure to cigarette smoke desensitized PTP1B activity that coincided with enhanced S100A9 secretion and inflammation in wild-type animals during RSV infection. S100A9 levels in human bronchoalveolar lavage fluid had an inverse relationship with lung function in healthy subjects, smokers, and COPD subjects. Fully differentiated human bronchial epithelial cells isolated from COPD donors cultured at the air liquid interface secreted more S100A9 than cells from healthy donors or smokers following RSV infection. Together, these findings show that reduced PTP1B responses contribute to disease symptoms in part by enhancing S100A9 expression during viral-associated COPD exacerbations.
Abstract
The detection, identification, and localization of illicit radiological and nuclear material continue to be key components of nuclear non-proliferation and nuclear security efforts around ...the world. Networks of radiation detectors deployed at strategic locations in urban environments have the potential to provide continuous radiological/nuclear (R/N) surveillance and provide high probabilities of intercepting threat sources. The integration of contextual information from sensors such as video, Lidar, and meteorological sensors can provide significantly enhanced situational awareness, and improved detection and localization performance through the fusion of the radiological and contextual data. In this work, we present details of our work to establish a city-scale multi-sensor network testbed for intelligent, adaptive R/N detection in urban environments, and develop new techniques that enable city-scale source detection, localization, and tracking.
Viral infections are considered a major driving factor of chronic obstructive pulmonary disease (COPD) exacerbations and thus contribute to disease morbidity and mortality. Respiratory syncytial ...virus (RSV) is a frequently detected pathogen in the respiratory tract of COPD patients during an exacerbation. We previously demonstrated in a murine model that leukemia inhibitory factor (LIF) expression was increased in the lungs during RSV infection. Subduing LIF signaling in this model enhanced lung injury and airway hypersensitivity. In this study, we investigated lung LIF levels in COPD patient samples to determine the impact of disease status and cigarette smoke exposure on LIF expression.
Bronchoalveolar lavage fluid (BALF) was obtained from healthy never smokers, smokers, and COPD patients, by written informed consent. Human bronchial epithelial (HBE) cells were isolated from healthy never smokers and COPD patients, grown at the air-liquid interface and infected with RSV or stimulated with polyinosinic:polycytidylic acid (poly (i:c)). Mice were exposed to cigarette smoke daily for 6 months and were subsequently infected with RSV. LIF expression was profiled in all samples.
In human BALF, LIF protein was significantly reduced in both smokers and COPD patients compared to healthy never smokers. HBE cells isolated from COPD patients produced less LIF compared to never smokers during RSV infection or poly (i:c) stimulation. Animals exposed to cigarette smoke had reduced lung levels of LIF and its corresponding receptor, LIFR. Smoke-exposed animals had reduced LIF expression during RSV infection. Two possible factors for reduced LIF levels were increased LIF mRNA instability in COPD epithelia and proteolytic degradation of LIF protein by serine proteases.
Cigarette smoke is an important modulator for LIF expression in the lungs. Loss of LIF expression in COPD could contribute to a higher degree of lung injury during virus-associated exacerbations.
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