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Bhatia S.,University of Pittsburgh | Fei M.,University of Pittsburgh | Yarlagadda M.,University of Pittsburgh | Qi Z.,University of Pittsburgh | And 10 more authors.

The ubiquitous fungus Aspergillus fumigatus is associated with chronic diseases such as invasive pulmonary aspergillosis in immunosuppressed patients and allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis or severe asthma. Because of constant exposure to this fungus, it is critical for the host to exercise an immediate and decisive immune response to clear fungal spores to ward off disease. In this study, we observed that rapidly after infection by A. fumigatus, alveolar macrophages predominantly express Arginase 1 (Arg1), a key marker of alternatively activated macrophages (AAMs). The macrophages were also found to express Ym1 and CD206 that are also expressed by AAMs but not NOS2, which is expressed by classically activated macrophages. The expression of Arg1 was reduced in the absence of the known signaling axis, IL-4Rα/STAT6, for AAM development. While both Dectin-1 and TLR expressed on the cell surface have been shown to sense A. fumigatus, fungus-induced Arg1 expression in CD11c+ alveolar macrophages was not dependent on either Dectin-1 or the adaptor MyD88 that mediates intracellular signaling by most TLRs. Alveolar macrophages from WT mice efficiently phagocytosed fungal conidia, but those from mice deficient in Dectin-1 showed impaired fungal uptake. Depletion of macrophages with clodronate-filled liposomes increased fungal burden in infected mice. Collectively, our studies suggest that alveolar macrophages, which predominantly acquire an AAM phenotype following A. fumigatus infection, have a protective role in defense against this fungus. © 2011 Bhatia et al. Source

Inoue T.,Kohnan Hospital | Shimizu H.,Tohoku University | Fujimura M.,Kohnan Hospital | Saito A.,Tohoku University | And 3 more authors.
Clinical Neurology and Neurosurgery

Object: The brain temperature at rest is determined by the balance between heat produced by cerebral energy turnover, which is identical to cerebral metabolism, and heat that is removed, primarily by cerebral blood flow. The present study investigated whether brain temperature measured by proton magnetic resonance (MR) spectroscopy can detect cerebral hemodynamic impairment in patients with arteriovenous malformations (AVMs) as shown by single photon emission computed tomography (SPECT). Methods: Brain temperature, cerebral blood flow, and cerebrovascular reactivity were measured using proton MR spectroscopy and SPECT in five healthy volunteers and six patients with AVMs. Regions of interest were selected adjacent to the AVMs and in the corresponding contralateral region. Results: Brain temperature around AVMs was calculated in all subjects using MR spectroscopy. The mean brain temperature in volunteers was 37.1 ± 0.41 °C. A significant correlation was observed between brain temperature ratio (affected side/contralateral side) and cerebrovascular reactivity ratio (affected side/contralateral side) (r = -0.82, p = 0.0480). Conclusion: Brain temperature measured by proton MR spectroscopy can detect cerebral hemodynamic impairment in patients with AVMs. Further investigations regarding the relationships between brain temperature and clinical feature in patients with AVMs are needed. © 2012 Elsevier B.V. Source

Kagawa Y.,Immunology Frontier Research Center
Nihon Geka Gakkai zasshi

Intravital imaging using two-photon laser scanning microscopy (TPSLM) can visualize the cellular dynamics in a living body. By recording spatiotemporal images, this technique allows the detection of unknown cell movements and related unknown phenomena in an environment in which blood circulation is maintained. Because of these advantages, this multidimensional in vivo analytical technique has attracted attention from various research fields. TPSLM has also been introduced in cancer research and utilized to visualize cancer cell movements. By determining cancer dynamics in vivo, it is expected that new cancer movement-related molecules will be discovered, which could be novel therapeutic targets. This article introduces the TPSLM imaging technique and method of molecular analysis using this imaging system. Source

Nishimura T.,Tokyo Medical and Dental University | Nishimura T.,University of Tokyo | Kaizuka T.,Tokyo Medical and Dental University | Cadwell K.,New York University | And 7 more authors.
EMBO Reports

Autophagosome formation is a dynamic process that is strictly controlled by autophagy-related (Atg) proteins. However, how these Atg proteins are recruited to the autophagosome formation site or autophagic membranes remains poorly understood. Here, we found that FIP200, which is involved in proximal events, directly interacts with Atg16L1, one of the downstream Atg factors, in an Atg14-and phosphatidylinositol 3-kinase-independent manner. Atg16L1 deletion mutants, which lack the FIP200-interacting domain, are defective in proper membrane targeting. Thus, FIP200 regulates not only early events but also late events of autophagosome formation through direct interaction with Atg16L1. © 2013 European Molecular Biology Organization. Source

Proudfoot O.,Burnet Institute | Esparon S.,Burnet Institute | Tang C.-K.,Immunology Frontier Research Center | Laurie K.,Collaborating Center for Reference and Research on Influenza | And 4 more authors.
BMC Infectious Diseases

Background: H1N1 influenza viruses mutate rapidly, rendering vaccines developed in any given year relatively ineffective in subsequent years. Thus it is necessary to generate new vaccines every year, but this is time-consuming and resource-intensive. Should a highly virulent influenza strain capable of human-to-human transmission emerge, these factors will severely limit the number of people that can be effectively immunised against that strain in time to prevent a pandemic. An adjuvant and mode of administration capable of rendering ordinarily unprotective vaccine doses protective would thus be highly advantageous. Methods: The carbohydrate mannan was conjugated to whole inactivated H1N1 influenza virus at a range of ratios, and mixed with it at a range of ratios, and various doses of the resulting preparations were administered to mice via the intranasal (IN) route. Serum immunity was assessed via antigen-specific IgG ELISA and the haemagglutination-inhibition (HI) assay, and mucosal immunity was assessed via IgA ELISA of bronchio-alveolar lavages. Results: IN-administered inactivated H1N1 mixed with mannan induced higher serum IgG and respiratory-tract IgA than inactivated H1N1 conjugated to mannan, and HIN1 alone. Adjuvantation was mannan-dose-dependent, with 100μg of mannan adjuvanting 1μg of H1N1 more effectively than 10 or 50μg of mannan. Serum samples from mice immunised with 1μg H1N1 adjuvanted with 10μg mannan did not inhibit agglutination of red blood cells (RBCs) at a dilution factor of 10 in the HI assay, but samples resulting from adjuvantation with 50 and 100μg mannan inhibited agglutination at dilution factors of≥40. Both serum IgG1 and IgG2a were induced by IN mannan-adjuvanted H1N1 vaccination, suggesting the induction of humoral and cellular immunity. Conclusions: Mixing 100μg of mannan with 1μg of inactivated H1N1 adjuvanted the vaccine in mice, such that IN immunisation induced higher serum IgG and respiratory tract IgA than immunisation with virus alone. The serum from mice thus immunised inhibited H1N1-mediated RBC agglutination strongly in vitro. If mannan similarly adjuvants low doses of influenza vaccine in humans, it could potentially be used for vaccine 'dose-sparing' in the event that a vaccine shortage arises from an epidemic involving a highly virulent human-to-human transmissable influenza strain. © 2015 Proudfoot et al.; licensee BioMed Central. Source

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