Phagocytosis of Aspergillus fumigatus by Human Bronchial Epithelial Cells Is Mediated by the Arp2/3 Complex and WIPF2

Aspergillus fumigatus is an opportunistic fungal pathogen capable of causing severe infection in humans. One of the limitations in our understanding of how A. fumigatus causes infection concerns the initial stages of infection, notably the initial interaction between inhaled spores or conidia and the human airway. Using publicly-available datasets, we identified the Arp2/3 complex and the WAS-Interacting Protein Family Member 2 WIPF2 as being potentially responsible for internalization of conidia by airway epithelial cells. Using a cell culture model, we demonstrate that RNAi-mediated knockdown of WIPF2 significantly reduces internalization of conidia into airway epithelial cells. Furthermore, we demonstrate that inhibition of Arp2/3 by a small molecule inhibitor causes similar effects. Using super-resolution fluorescence microscopy, we demonstrate that WIPF2 is transiently localized to the site of bound conidia. Overall, we demonstrate the active role of the Arp2/3 complex and WIPF2 in mediating the internalization of A. fumigatus conidia into human airway epithelial cells

Looking under the skin: multi-scale CT scanning of a peculiarly constructed cornett in the Rijksmuseum

Covered tightly by a thin leather skin, three early seventeenth-century cornetts from the collection of the Rijksmuseum were examined with the focus on their construction and manufacturing. One cornett of the three unexpectedly turned out to have a peculiar construction and to be made out of two sections of different wood species. The question arose whether this could be original or is the result of an extensive restoration. As the internal structure is not accessible for analysis and examination, multi-scale Computed Tomography (CT) scanning was employed to identify the exact regions of interest (ROI) and subsequently perform scans at a sufficiently high resolution in those areas. 3D images of the hollow spaces such as the tunnelling structure caused by the common furniture beetle (Anobium punctatum) criss-crossing the wood species could be computed from the 3D x-ray tomography reconstruction. This allowed to place the occurrence of the insect infestation after the joining of the two sections. Fine tool-marks, signs of construction and potential indications of earlier treatments could be visualized. These results were compared with the other two instruments of the same group and cross-referenced to instruments in other collections, in an attempt to answer questions about the instrument's authenticity and originality. While the unusual construction out of two wood species might be the result of an extensive repair, another possible hypothesis-based on the combination of the results-is that this unique choice of original manufacturing was intentional, possibly to avoid splitting of the wood when inserting the mouthpiece or to counteract undesired vibrations when played.Algorithms and the Foundations of Software technolog

The dual space: Concept and applications in cultural heritage

An important question in cultural heritage concerns the make process of an artifact. Understanding the make process provides insight related to the origin, techniques and craftsmanship used to make the artifact. Searching for tool marks or traces left by the artist’s hand is one way of retrieving clues related to the make process. X-ray computed tomography (CT) is a non-destructive tool that produces volumetric images of structures inside an artifact. However, interactively searching in large vol- umetric images for tool marks is a difficult, tedious and time consuming task. In this article, we introduce the concept of a dual space. The governing idea is that the dual space represents the air in the interior of an object. In the context of cultural heritage, the dual space represents those materials that first belonged to the object but have been removed during the make process. Our main goal of creating the dual space is to facilitate searching, inspection and interpretation of tool marks. We provide two examples of how the dual space can be used to study the make process

Integrating expert feedback on the spot in a time-efficient explorative CT scanning workflow for cultural heritage objects

Computed Tomography (CT) has proven itself as a powerful technique for analysing the internal structure of cultural heritage objects. The process followed by conservators and technical art historians for investigating an object is explorative: each time a new question is asked based on the outcome of the previous investigation. This workflow however conflicts with the static nature of CT imaging, where the planning, execution and image analysis for a single CT scan can take days, or even weeks. A new question often requires conducting a new experiment, repeating the process of planning, execution and image analysis. This means that the time that is needed to complete the investigation is often longer than originally anticipated. In addition, it brings up more practical challenges such as the transportation of the object, facility availability and dependence on the imaging operator, as well as the cost of running additional experiments. A much needed interactive imaging process, where the user can adapt the CT scanning process based on the insights discovered on the spot, is hard to accomplish. Therefore, in this paper we show how a time-efficient explorative workflow can be created for CT investigation of art objects, where the object can be inspected in 3D while still in the scanner, and based on the observations and the resulting new questions, the scanning procedure can be iteratively refined. We identify the technical requirements for a CT scanner that can address the diversity in cultural heritage objects (size, shape, material composition), and the need for adaptive steering of the scanning process required for an explorative workflow. Our approach has been developed through the interdisciplinary research projects The See-Through Museum and Impact4Art. We demonstrate the key concepts by showing results of art objects scanned at the FleX-ray Laboratory at CWI, Amsterdam

Exploring Definitions and Predictors of Severe Asthma Clinical Remission Post-Biologic in Adults.

RATIONALE: There is no consensus on criteria to include in an asthma remission definition in real-life. Factors associated with achieving remission post-biologic-initiation remain poorly understood. OBJECTIVES: To quantify the proportion of adults with severe asthma achieving multi-domain-defined remission post-biologic-initiation and identify pre-biologic characteristics associated with achieving remission which may be used to predict it. METHODS: This was a longitudinal cohort study using data from 23 countries from the International Severe Asthma Registry. Four asthma outcome domains were assessed in the 1-year pre- and post-biologic-initiation. A priori-defined remission cut-offs were: 0 exacerbations/year, no long-term oral corticosteroid (LTOCS), partly/well-controlled asthma, and percent predicted forced expiratory volume in one second ≥80%. Remission was defined using 2 (exacerbations + LTOCS), 3 (+control or +lung function) and 4 of these domains. The association between pre-biologic characteristics and post-biologic remission was assessed by multivariable analysis. MEASUREMENTS AND MAIN RESULTS: 50.2%, 33.5%, 25.8% and 20.3% of patients met criteria for 2, 3 (+control), 3 (+lung function) and 4-domain-remission, respectively. The odds of achieving 4-domain remission decreased by 15% for every additional 10-years asthma duration (odds ratio: 0.85; 95% CI: 0.73, 1.00). The odds of remission increased in those with fewer exacerbations/year, lower LTOCS daily dose, better control and better lung function pre-biologic-initiation. CONCLUSIONS: One in 5 patients achieved 4-domain remission within 1-year of biologic-initiation. Patients with less severe impairment and shorter asthma duration at initiation had a greater chance of achieving remission post-biologic, indicating that biologic treatment should not be delayed if remission is the goal. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Comparative effectiveness of Anti-IL5 and Anti-IgE biologic classes in patients with severe asthma eligible for both.

BACKGROUND: Patients with severe asthma may present with characteristics representing overlapping phenotypes, making them eligible for more than one class of biologic. Our aim was to describe the profile of adult patients with severe asthma eligible for both anti-IgE and anti-IL5/5R and to compare the effectiveness of both classes of treatment in real life. METHODS: This was a prospective cohort study that included adult patients with severe asthma from 22 countries enrolled into the International Severe Asthma registry (ISAR) who were eligible for both anti-IgE and anti-IL5/5R. The effectiveness of anti-IgE and anti-IL5/5R was compared in a 1:1 matched cohort. Exacerbation rate was the primary effectiveness endpoint. Secondary endpoints included long-term-oral corticosteroid (LTOCS) use, asthma-related emergency room (ER) attendance, and hospital admissions. RESULTS: In the matched analysis (n = 350/group), the mean annualized exacerbation rate decreased by 47.1% in the anti-IL5/5R group and 38.7% in the anti-IgE group. Patients treated with anti-IL5/5R were less likely to experience a future exacerbation (adjusted IRR 0.76; 95% CI 0.64, 0.89; p < 0.001) and experienced a greater reduction in mean LTOCS dose than those treated with anti-IgE (37.44% vs. 20.55% reduction; p = 0.023). There was some evidence to suggest that patients treated with anti-IL5/5R experienced fewer asthma-related hospitalizations (IRR 0.64; 95% CI 0.38, 1.08), but not ER visits (IRR 0.94, 95% CI 0.61, 1.43). CONCLUSIONS: In real life, both anti-IgE and anti-IL5/5R improve asthma outcomes in patients eligible for both biologic classes; however, anti-IL5/5R was superior in terms of reducing asthma exacerbations and LTOCS use

Exploring definitions and predictors of severe asthma clinical remission post-biologic in adults

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