Human bronchial epithelium controls TH2 responses by TH1-induced, nitric oxide-mediated STAT5 dephosphorylation: implications for the pathogenesis of asthma

Increased levels of NO in exhaled air in association with increased NO synthetase (NOS)2 expression in bronchial epithelial are hallmark features of asthma. It has been suggested that NO contributes to asthma pathogenesis by selective down-regulation of TH1 responses. We demonstrate, however, that NO can reversibly limit in vitro expansion of both human TH1 and TH2 CD4+ T cells. Mechanistically, NO induces cGMP-mediated reversible STAT5 dephosphorylation and therefore interferes with the IL-2R activation cascade. Human bronchial epithelial cells (HBEC) up-regulate NOS2 after stimulation with IFN-gamma secreted by TH1 CD4+ T cells and release NO, which inhibits both TH1 and TH2 cell proliferation. This reversible T cell growth arrest depends on NO because T cell proliferation is completely restored after in vitro blocking of NOS2 on HBEC. HBEC thus drive the effector end of a TH1-controlled feedback loop, which protects airway mucosal tissues at the potential lesional site in asthma from overwhelming CD4+ TH2 (and potentially TH1) responses following allergen exposure. Variations in the efficiency of this feedback loop provides a plausible mechanism to explain why only a subset of atopics sensitized to ubiquitous aeroallergens progress to expression of clinically relevant levels of airways inflammation.

Scrivere di architettura intorno al 1780: Andrea Memmo e Francesco Milizia tra il Veneto e Roma

Andrea Memmo ist in der Geschichte der Architekturtheorie vor allem deswegen bekannt, weil er durch die Veröffentlichung der 'Elementi d'architettura lodoliana, ossia l'arte del fabricare con solidità scientifica e con eleganza non capricciosa' (Rom 1786) entscheidend dazu beigetragen hat, die originellen architektonischen Konzepte der Nachwelt zu überliefern, die der venezianische Franziskaner Carlo Lodoli zwischen 1730 und 1750 mündlich verbreitet hatte. Der vorliegende Beitrag unternimmt es, anhand des bislang für verloren gehaltenen 'Piano Accademico', den Memmo um 1767 für die venezianische Akademie zum Zwecke der Unterrichtsreform der bildenden Künste (Skulptur, Malerei und Architektur) ausgearbeitet hatte, klarzustellen, welche wichtige Rolle der Aufenthalt in Rom für Memmo gespielt hat. Dies wird auch durch die Briefe belegt, die er während der Ausarbeitung seines Werkes über Lodoli verfasst hatte. Im Rom der 1780er Jahre waren für ihn ausschlaggebend 1. die Beziehungen zur dortigen Accademia di S. Luca und 2. seine Freundschaft zum spanische Botschafter José Nicolas de Azara. Azara hatte ihn dazu ermutigt, über den Padre Lodoli zu schreiben, um dessen Gedanken denen des mit Azara befreundeten Francesco Milizia gegenüberzustellen.

Entrepreneurship in a Hub-and-Spoke Industrial District: Firm Survey Evidence from Seattle's Technology Industry

Mayer H. Entrepreneurship in a hub-and-spoke industrial district: firm survey evidence from Seattle's technology industry, Regional Studies. The paper investigates entrepreneurial dynamics in a hub-and-spoke industrial district. Using data on the genealogy of high-technology firms in Seattle, Washington State, the study examines the ways in which entrepreneurial firms relate to their parent firms and the role of agglomeration economies. The results illustrate that entrepreneurship is an important vehicle for the diversification of such a district. When compared, hub-related spinoffs such as those founded by former Microsoft employees do not differ much from other start-ups. The differences between Microsoft spinoffs and start-ups are very limited; both diversify the regional economy by entering new markets when compared with their parents.

Combined inhibition of complement C5 and CD14 markedly attenuates inflammation, thrombogenicity, and hemodynamic changes in porcine sepsis

Complement and the TLR family constitute two important branches of innate immunity. We previously showed attenuating effects on inflammation and thromogenicity by inhibiting the TLR coreceptor CD14 in porcine sepsis. In the present study, we explored the effect of the C5 and leukotriene B4 inhibitor Ornithodoros moubata complement inhibitor (OmCI; also known as coversin) alone and combined with anti-CD14 on the early inflammatory, hemostatic, and hemodynamic responses in porcine Escherichia coli-induced sepsis. Pigs were randomly allocated to negative controls (n = 6), positive controls (n = 8), intervention with OmCI (n = 8), or with OmCI and anti-CD14 (n = 8). OmCI ablated C5 activation and formation of the terminal complement complex and significantly decreased leukotriene B4 levels in septic pigs. Granulocyte tissue factor expression, formation of thrombin-antithrombin complexes (p < 0.001), and formation of TNF-α and IL-6 (p < 0.05) were efficiently inhibited by OmCI alone and abolished or strongly attenuated by the combination of OmCI and anti-CD14 (p < 0.001 for all). Additionally, the combined therapy attenuated the formation of plasminogen activator inhibitor-1 (p < 0.05), IL-1β, and IL-8, increased the formation of IL-10, and abolished the expression of wCD11R3 (CD11b) and the fall in neutrophil cell count (p < 0.001 for all). Finally, OmCI combined with anti-CD14 delayed increases in heart rate by 60 min (p < 0.05) and mean pulmonary artery pressure by 30 min (p < 0.01). Ex vivo studies confirmed the additional effect of combining anti-CD14 with OmCI. In conclusion, upstream inhibition of the key innate immunity molecules, C5 and CD14, is a potential broad-acting treatment regimen in sepsis as it efficiently attenuated inflammation and thrombogenicity and delayed hemodynamic changes.

NADPH oxidase-independent formation of extracellular DNA traps by basophils

Basophils are primarily associated with a proinflammatory and immunoregulatory role in allergic diseases and parasitic infections. Recent studies have shown that basophils can also bind various bacteria both in the presence and the absence of opsonizing Abs. In this report, we show that both human and mouse basophils are able to produce mitochondrial reactive oxygen species and to form extracellular DNA traps upon IL-3 priming and subsequent activation of the complement factor 5 a receptor or FcεRI. Such basophil extracellular traps (BETs) contain mitochondrial, but not nuclear DNA, as well as the granule proteins basogranulin and mouse mast cell protease 8. BET formation occurs despite the absence of any functional NADPH oxidase in basophils. BETs can be found in both human and mouse inflamed tissues, suggesting that they also play a role under in vivo inflammatory conditions. Taken together, these findings suggest that basophils exert direct innate immune effector functions in the extracellular space.

Exercitatio academica De lingua Ebraea maturius addiscenda

Wittenberg, Univ., Diss., 1733

Gerichtliche Verhör derer Zeugen der Auferstehung Jesu : worinnen nicht nur des Woolstons Einwürffe, die er in seinen so genannten sechs Discoursen anführet, sondern auch diejenigen, welche so wohl er, als andere ... hrsg., gantz unparteyisch erwogen werden

[Thomas Sherlock]. Aus d. Engl. übers.

Human IgA Fc receptor FcαRI (CD89) triggers different forms of neutrophil death depending on the inflammatory microenvironment

FcαRI (CD89), the human Fc receptor for IgA, is highly expressed on neutrophil granulocytes. In this study, we show that FcαRI induces different forms of neutrophil death, depending on the inflammatory microenvironment. The susceptibility of inflammatory neutrophils from sepsis or rheumatoid arthritis toward death induced by specific mAb, or soluble IgA at high concentrations, was enhanced. Although unstimulated cells experienced apoptosis following anti-FcαRI mAb stimulation, preactivation with cytokines or TLR agonists in vitro enhanced FcαRI-mediated death by additional recruitment of caspase-independent pathways, but this required PI3K class IA and MAPK signaling. Transmission electron microscopy of FcαRI-stimulated cells revealed cytoplasmic changes with vacuolization and mitochondrial swelling, nuclear condensation, and sustained plasma membrane. Coculture experiments with macrophages revealed anti-inflammatory effects of the partially caspase-independent death of primed cells following FcαRI engagement. Our data suggest that FcαRI has the ability to regulate neutrophil viability and to induce different forms of neutrophils depending on the inflammatory microenvironment and specific characteristics of the ligand-receptor interactions. Furthermore, these findings have potential implications for FcαRI-targeted strategies to treat neutrophil-associated inflammatory diseases.