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Ryo Okuda,1 Tamiko Takemura,2 Toshihiro Misumi,3 Eri Hagiwara,1 Takashi Ogura1 1Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan; 2Department of Pathology, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan; 3Department of Data Science, National Cancer Center Hospital East, Chiba, JapanCorrespondence: Ryo Okuda, Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, 6-16-1 Tomioka-higashi, Kanazawa-ku, Yokohama, Japan, Tel +81-45-701-9581, Email b980013@yahoo.co.jpBackground: In the two fibrotic hypersensitivity pneumonitis (fHP) diagnostic guidelines, the multidisciplinary discussion (MDD) is required to be performed in diagnosis of fHP, as in idiopathic pulmonary fibrosis (IPF) diagnostic guideline. Although some patients with fHP can improve disease condition during antigen avoidance, which can facilitate the diagnosis of fHP, it is unclear if MDD is necessary in all patients with suspected fHP who improved an antigen avoidance.Objective: To investigate the diagnosis of fHP via MDD with positive antigen avoidance tests (AATs) and the clinical diagnosis with positive AATs.Methods: A single-center, retrospective study was conducted. Between 2012 and 2019, patients with fHP were enrolled in the study. Patients in the MDD diagnostic group consisted of patients diagnosed with MDD, including histopathology findings and positive ATTs, and patients in the clinical diagnostic group were diagnosed by two respiratory physicians and had positive ATTs.Results: AAT was performed on 72 of 219 patients, and 58 had positive AATs. The study included 37 patients in the MDD diagnosis group and 21 patients in the clinical diagnosis group. No significant differences in overall survival (OS) were detected between the two groups (HR: 1.99 [95% CI: 0.82‒4.83], p = 0.127). The conducting MDD was not a risk factor for OS; only < 79% forced vital capacity was a risk factor in the multivariate Cox hazard regression analysis. No significant difference in annual changes of forced vital capacity, diffusion of the lung for carbon monoxide and Krebs von den Lungen-6 between the MDD diagnostic and the clinical diagnostic groups were observed (p = 0.41, 0.79, and 0.81, respectively).Conclusion: In patients with positive AATs, the disease progression of the MDD diagnostic and the clinical diagnostic groups were similar. Therefore, MDD could not be necessary in all patients with suspected fHP who had positive AATs.Keywords: chronic hypersensitivity pneumonitis, diagnostic method, hypersensitivity pneumonitis, multidisciplinary team, subacute hypersensitivity pneumonitis

Liming Xu,1,2,* Mo Dan,1,* Anliang Shao,1 Xiang Cheng,1,3 Cuiping Zhang,4 Robert A Yokel,5 Taro Takemura,6 Nobutaka Hanagata,6 Masami Niwa,7,8 Daisuke Watanabe7,81National Institutes for Food and Drug Control, No 2, Temple of Heaven, Beijing, 2School of Information and Engineering, Wenzhou Medical University, Wenzhou, 3School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu, 4Beijing Neurosurgical Institute, Capital Medical University, Beijing, People’s Republic of China; 5College of Pharmacy, University of Kentucky, Lexington, KY, USA; 6Nanotechnology Innovation Station for Nanoscale Science and Technology, National Institute for Materials Science, Tsukuba, Ibaraki, 7Department of Pharmacology, Nagasaki University, 8BBB Laboratory, PharmaCo-Cell Company, Ltd., Nagasaki, Japan*These authors contributed equally to this workBackground: Silver nanoparticles (Ag-NPs) can enter the brain and induce neurotoxicity. However, the toxicity of Ag-NPs on the blood–brain barrier (BBB) and the underlying mechanism(s) of action on the BBB and the brain are not well understood.Method: To investigate Ag-NP suspension (Ag-NPS)-induced toxicity, a triple coculture BBB model of rat brain microvascular endothelial cells, pericytes, and astrocytes was established. The BBB permeability and tight junction protein expression in response to Ag-NPS, NP-released Ag ions, and polystyrene-NP exposure were investigated. Ultrastructural changes of the microvascular endothelial cells, pericytes, and astrocytes were observed using transmission electron microscopy (TEM). Global gene expression of astrocytes was measured using a DNA microarray.Results: A triple coculture BBB model of primary rat brain microvascular endothelial cells, pericytes, and astrocytes was established, with the transendothelial electrical resistance values >200 Ω·cm2. After Ag-NPS exposure for 24 hours, the BBB permeability was significantly increased and expression of the tight junction (TJ) protein ZO-1 was decreased. Discontinuous TJs were also observed between microvascular endothelial cells. After Ag-NPS exposure, severe mitochondrial shrinkage, vacuolations, endoplasmic reticulum expansion, and Ag-NPs were observed in astrocytes by TEM. Global gene expression analysis showed that three genes were upregulated and 20 genes were downregulated in astrocytes treated with Ag-NPS. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the 23 genes were associated with metabolic processes, biosynthetic processes, response to stimuli, cell death, the MAPK pathway, and so on. No GO term and KEGG pathways were changed in the released-ion or polystyrene-NP groups. Ag-NPS inhibited the antioxidant defense of the astrocytes by increasing thioredoxin interacting protein, which inhibits the Trx system, and decreasing Nr4a1 and Dusp1. Meanwhile, Ag-NPS induced inflammation and apoptosis through modulation of the MAPK pathway or B-cell lymphoma-2 expression or mTOR activity in astrocytes.Conclusion: These results draw our attention to the importance of Ag-NP-induced toxicity on the neurovascular unit and provide a better understanding of its toxicological mechanisms on astrocytes.Keywords: Ag nanoparticles, astrocytes, BBB model, global gene expression analysis, antioxidant defense

Micro pixel chambers (μ-PIC) are gaseous two-dimensional imaging detectors originally manufactured using printed circuit board (PCB) technology. They are used in MeV gamma-ray astronomy, medicalimaging, neutron imaging, the search for dark matter, and dose monitoring. The position resolution of the present μ-PIC is approximately 120 μm (RMS), however some applications require a fine position resolution of less than 100 μm. To this end, we have started to develop a μ-PIC based on micro electro mechanical system (MEMS) technology, which provides better manufacturing accuracy than PCB technology. Our simulation predicted the gains of MEMS μ-PICs to be twice those of PCB μ-PICs at the same anode voltage. We manufactured two MEMS μ-PICs and tested them to study their behavior. In these experiments, we successfully operated the fabricatedMEMS μ-PICs and we achieved a maximum gain of approximately 7×103 and collected their energy spectra under irradiation of X-rays from 55Fe. However, the measured gains of the MEMS μ-PICs were less than half of the values predicted in the simulations. We postulated that the gains of the MEMS μ-PICs are diminished by the effect of the silicon used as a semiconducting substrate.

Over the past few decades, the geographical distribution of emissions of substances that alter the atmospheric energy balance has changed due to economic growth and air pollution regulations. Here, we show the resulting changes to aerosol and ozone abundances and their radiative forcing using recently updated emission data for the period 1990-2015, as simulated by seven global atmospheric composition models. The models broadly reproduce large-scale changes in surface aerosol and ozone based on observations (e.g.-1 to-3%yr-1 in aerosols over the USA and Europe). The global mean radiative forcing due to ozone and aerosol changes over the 1990-2015 period increased by +0.17±0.08Wm-2, with approximately one-third due to ozone. This increase is more strongly positive than that reported in IPCC AR5. The main reasons for the increased positive radiative forcing of aerosols over this period are the substantial reduction of global mean SO2 emissions, which is stronger in the new emission inventory compared to that used in the IPCC analysis, and higher black carbon emissions.

This paper evaluates the current status of global modeling of the organic aerosol (OA) in the troposphere and analyzes the differences between models as well as between models and observations. Thirty-one global chemistry transport models (CTMs) and general circulation models (GCMs) have participated in this intercomparison, in the framework of AeroCom phase II. The simulation of OA varies greatly between models in terms of the magnitude of primary emissions, secondary OA (SOA) formation, the number of OA species used (2 to 62), the complexity of OA parameterizations (gas-particle partitioning, chemical aging, multiphase chemistry, aerosol microphysics), and the OA physical, chemical and optical properties. The diversity of the global OA simulation results has increased since earlier AeroCom experiments, mainly due to the increasing complexity of the SOA parameterization in models, and the implementation of new, highly uncertain, OA sources. Diversity of over one order of magnitude exists in the modeled vertical distribution of OA concentrations that deserves a dedicated future study. Furthermore, although the OA / OC ratio depends on OA sources and atmospheric processing, and is important for model evaluation against OA and OC observations, it is resolved only by a few global models. The median global primary OA (POA) source strength is 56 Tg a-1 (range 34-144 Tg a-1) and the median SOA source strength (natural and anthropogenic) is 19 Tg a-1 (range 13-121 Tg a-1). Among the models that take into account the semi-volatile SOA nature, the median source is calculated to be 51 Tg a-1 (range 16-121 Tg a-1), much larger than the median value of the models that calculate SOA in a more simplistic way (19 Tg a-1; range 13-20 Tg a-1, with one model at 37 Tg a-1). The median atmospheric burden of OA is 1.4 Tg (24 models in the range of 0.6-2.0 Tg and 4 between 2.0 and 3.8 Tg), with a median OA lifetime of 5.4 days (range 3.8-9.6 days). In models that reported both OA and sulfate burdens, the median value of the OA/sulfate burden ratio is calculated to be 0.77; 13 models calculate a ratio lower than 1, and 9 models higher than 1. For 26 models that reported OA deposition fluxes, the median wet removal is 70 Tg a-1 (range 28-209 Tg a-1), which is on average 85% of the total OA deposition. Fine aerosol organic carbon (OC) and OA observations from continuous monitoring networks and individual field campaigns have been used for model evaluation. At urban locations, the model-observation comparison indicates missing knowledge on anthropogenic OA sources, both strength and seasonality. The combined model-measurements analysis suggests the existence of increased OA levels during summer due to biogenic SOA formation over large areas of the USA that can be of the same order of magnitude as the POA, even at urban locations, and contribute to the measured urban seasonal pattern. Global models are able to simulate the high secondary character of OA observed in the atmosphere as a result of SOA formation and POA aging, although the amount of OA present in the atmosphere remains largely underestimated, with a mean normalized bias (MNB) equal to -0.62 (-0.51) based on the comparison against OC (OA) urban data of all models at the surface, -0.15 (+0.51) when compared with remote measurements, and -0.30 for marine locations with OC data. The mean temporal correlations across all stations are low when compared with OC (OA) measurements: 0.47 (0.52) for urban stations, 0.39 (0.37) for remote stations, and 0.25 for marine stations with OC data. The combination of high (negative) MNB and higher correlation at urban stations when compared with the low MNB and lower correlation at remote sites suggests that knowledge about the processes that govern aerosol processing, transport and removal, on top of their sources, is important at the remote stations. There is no clear change in model skill with increasing model complexity with regard to OC or OA mass concentration. However, the complexity is needed in models in order to distinguish between anthropogenic and natural OA as needed for climate mitigation, and to calculate the impact of OA on climate accurately.

This study presents the results of a broad intercomparison of a total of 15 global aerosol models within the AeroCom project. Each model is compared to observations related to desert dust aerosols, their direct radiative effect, and their impact on the biogeochemical cycle, i.e., aerosol optical depth (AOD) and dust deposition. Additional com parisons to Angstrom exponent (AE), coarse mode AOD and dust surface concentrations are included to extend the assessment of model performance and to identify common biases present in models. These data comprise a benchmark dataset that is proposed for model inspection and future dust model development. There are large differences among the global models that simulate the dust cycle and its impact on climate. In general, models simulate the climatology of vertically integrated parameters (AOD and AE) within a factor of two whereas the total deposition and surface concentration are reproduced within a factor of 10. In addition, smaller mean normalized bias and root mean square errors are obtained for the climatology of AOD and AE than for total deposition and surface concentration. Characteristics of the datasets used and their uncertainties may influence these differences. Large uncertainties still exist with respect to the deposition fluxes in the southern oceans. Further measurements and model studies are necessary to assess the general model performance to reproduce dust deposition in ocean regions sensible to iron contributions. Models overestimate the wet deposition in regions dominated by dry deposition. They generally simulate more realistic surface concentration at stations downwind of the main sources than at remote ones. Most models simulate the gradient in AOD and AE between the different dusty regions. However the seasonality and magnitude of both variables is better simulated at African stations than Middle East ones. The models simulate the offshore transport of West Africa throughout the year but they overestimate the AOD and they transport too fine particles. The models also reproduce the dust transport across the Atlantic in the summer in terms of both AOD and AE but not so well in winter-spring nor the southward displacement of the dust cloud that is responsible of the dust transport into South America. Based on the dependency of AOD on aerosol burden and size distribution we use model bias with respect to AOD and AE to infer the bias of the dust emissions in Africa and the Middle East. According to this analysis we suggest that a range of possible emissions for North Africa is 400 to 2200 Tg yr(-1) and in the Middle East 26 to 526 Tg yr(-1)

Aerosols affect the global budgets of O3, OH, and CH4 in part through their alteration of photolysis rates and in part through their direct chemical interactions with gases (i.e., “heterogeneous chemistry”). The first effect is evaluated here with a global tropospheric chemistry transport model using recently developed global climatologies of tropospheric aerosols: a satellite-derived aerosol climatology over the oceans by advanced very high resolution radiometer and a model-generated climatology for land plus oceans by the Center for Climate System Research. Globally averaged, the impact of aerosols on photolysis alone is to increase tropospheric O3 by 0.63 Dobson units and increase tropospheric CH4 by 130 ppb (via tropospheric OH decreases of 8%). These greenhouse gas increases lead to an aerosol indirect effect (counting both natural and anthropogenic aerosols) of +0.08 W/m2. Although the CH4 increases are, of course, global, the changes in tropospheric OH and O3 are mainly regional, with the largest impacts in northwest Africa for January and in India and southern Africa for July. The influence of aerosols is greater in July than in January and greater in the Northern Hemisphere than in the Southern Hemisphere, as expected given the pollution sources in the Northern Hemisphere. The predominant impact is due to the aerosols over land; aerosols over the ocean contribute less than a third to globally integrated changes.

In the subtropical North Pacific, the east‐west gradient of iron deposition as atmospheric Asian dust strongly affects the zonal distribution of biological N2 fixation activity in numerical models, but the in‐situ relationship at a basin‐scale is not well examined. We examined the trans‐Pacific zonal variation in N2 fixation activity on 23°N in summer along with environmental parameters that potentially influence diazotrophy. Dissolved inorganic iron (DFe) was consistently low (<0.4 nM) throughout the transect. The atmospheric dust iron (dust‐Fe) flux increased westward, whereas phosphate and labile phosphoric monoesters in the surface decreased westward. N2 fixation varied between 34.6 and 298 μmol‐N m−2 d−1 and was high (>200 μmol‐N m−2 d−1) in the central area (150–180°W). N2 fixation rates significantly increased with dust‐Fe input only in the western area (137–180°E), whereas the contribution of DFe diffused from below the euphotic zone was often larger in the eastern area (120–170°W). N2 fixation was considerably low in the phosphate‐depleted western area despite the excess amount of iron relative to phosphate, and it increased with the labile phosphoric monoesters stock. These indicated that N2 fixation was primarily limited by phosphorus in the western area, though this activity also increased with iron supply from dust, likely due to phosphorus‐iron co‐limitation. In contrast, in the phosphorus‐repleted eastern area, iron supplied from dust and below the euphotic zone appeared to limit N2 fixation. Overall, N2 fixation in the subtropical North Pacific was likely limited by zonally different factors relating to iron and phosphorus availability. Plain Language Summary: N2 fixation, a process that converts N2 gas into ammonia, substantially affects biological production in subtropical ecosystems, where nitrogenous nutrients are scarce. The availability of both iron and phosphorus are primary factors controlling the growth of N2‐fixing organisms. In North Pacific subtropical waters, iron input as atmospheric Asian dust is considered to control the east‐west variation in N2 fixation; however, their relationship is not well‐examined. Here, we investigated the trans‐Pacific distribution of N2 fixation activity with iron and phosphorus availability. Our results show that dust input correlates with N2 fixation in the western area (137–180°E), which is in contrast with the eastern area (120–170°W), where vertically diffused iron was also important. In the phosphate‐depleted western area, N2 fixation positively correlated with the proxies of phosphorus supply, suggesting phosphorus limitation. This indicates phosphorus availability substantially controls the zonal distribution of N2 fixation in the subtropical North Pacific through co‐limitation with iron. The limitations are relaxed in the central area (150–180°W), likely due to elevated nutrient supply caused by bottom topography, resulting in a peak in N2 fixation. Therefore, the dynamics of both iron and phosphorus must be considered simultaneously to predict the response of N2 fixation to environmental changes. Key Points: Along the zonal transect in the subtropical North Pacific, N2 fixation activity was high in the central area (150–180°W)The central North Pacific was characterized by intermediate iron and phosphorus supply in the euphotic zoneEast‐west gradient of phosphorus availability controls the N2 fixation in the North Pacific through likely co‐limitation with iron [ABSTRACT FROM AUTHOR]