Pneumocystis cell wall β-glucan stimulates calcium-dependent signaling of IL-8 secretion by human airway epithelial cells

<p>Abstract</p> <p>Background</p> <p>Respiratory failure secondary to alveolar inflammation during <it>Pneumocystis </it>pneumonia is a major cause of death in immunocompromised patients. Neutrophil infiltration in the lung of patients with <it>Pneumocystis </it>infection predicts severity of the infection and death. Several previous studies indicate that airway epithelial cells release the neutrophil chemoattractant proteins, MIP-2 (rodents) and IL-8 (humans), in response to <it>Pneumocystis </it>and purified <it>Pneumocystis </it>cell wall β-glucans (PCBG) through the NF-κB-dependent pathway. However, little is known about the molecular mechanisms that are involved in the activation of airway epithelium cells by PCBG resulting in the secretion of IL-8.</p> <p>Method</p> <p>To address this, we have studied the activation of different calcium-dependent mitogen-activated protein kinases (MAPKs) in 1HAEo^-cells, a human airway epithelial cell line.</p> <p>Results</p> <p>Our data provide evidence that PCBG induces phosphorylation of the MAPKs, ERK, and p38, the activation of NF-κB and the subsequently secretion of IL-8 in a calcium-dependent manner. Further, we evaluated the role of glycosphingolipids as possible receptors for β-glucans in human airway epithelial cells. Preincubation of the cells with D-<it>threo</it>-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) a potent inhibitor of the glycosphingolipids synthesis, prior to PCBG stimulation, significantly decreased IL-8 production.</p> <p>Conclusion</p> <p>These data indicate that PCBG activates calcium dependent MAPK signaling resulting in the release of IL-8 in a process that requires glycosphingolipid for optimal signaling.</p

Echinocandin Treatment of Pneumocystis Pneumonia in Rodent Models Depletes Cysts Leaving Trophic Burdens That Cannot Transmit the Infection

Fungi in the genus Pneumocystis cause pneumonia (PCP) in hosts with debilitated immune systems and are emerging as co-morbidity factors associated with chronic diseases such as COPD. Limited therapeutic choices and poor understanding of the life cycle are a result of the inability of these fungi to grow outside the mammalian lung. Within the alveolar lumen, Pneumocystis spp., appear to have a bi-phasic life cycle consisting of an asexual phase characterized by binary fission of trophic forms and a sexual cycle resulting in formation of cysts, but the life cycle stage that transmits the infection is not known. The cysts, but not the trophic forms, express β -1,3-D-glucan synthetase and contain abundant β -1,3-D-glucan. Here we show that therapeutic and prophylactic treatment of PCP with echinocandins, compounds which inhibit the synthesis of β -1,3-D-glucan, depleted cysts in rodent models of PCP, while sparing the trophic forms which remained in significant numbers. Survival was enhanced in the echincandin treated mice, likely due to the decreased β -1,3-D-glucan content in the lungs of treated mice and rats which coincided with reductions of cyst numbers, and dramatic remodeling of organism morphology. Strong evidence for the cyst as the agent of transmission was provided by the failure of anidulafungin-treated mice to transmit the infection. We show for the first time that withdrawal of anidulafungin treatment with continued immunosuppression permitted the repopulation of cyst forms. Treatment of PCP with an echinocandin alone will not likely result in eradication of infection and cessation of echinocandin treatment while the patient remains immunosuppressed could result in relapse. Importantly, the echinocandins provide novel and powerful chemical tools to probe the still poorly understood bi-phasic life cycle of this genus of fungal pathogens

Study of the doubly charmed tetraquark T+cc

Quantum chromodynamics, the theory of the strong force, describes interactions of coloured quarks and gluons and the formation of hadronic matter. Conventional hadronic matter consists of baryons and mesons made of three quarks and quark-antiquark pairs, respectively. Particles with an alternative quark content are known as exotic states. Here a study is reported of an exotic narrow state in the D0D0π+ mass spectrum just below the D*+D0 mass threshold produced in proton-proton collisions collected with the LHCb detector at the Large Hadron Collider. The state is consistent with the ground isoscalar T+cc tetraquark with a quark content of ccu⎯⎯⎯d⎯⎯⎯ and spin-parity quantum numbers JP = 1+. Study of the DD mass spectra disfavours interpretation of the resonance as the isovector state. The decay structure via intermediate off-shell D*+ mesons is consistent with the observed D0π+ mass distribution. To analyse the mass of the resonance and its coupling to the D*D system, a dedicated model is developed under the assumption of an isoscalar axial-vector T+cc state decaying to the D*D channel. Using this model, resonance parameters including the pole position, scattering length, effective range and compositeness are determined to reveal important information about the nature of the T+cc state. In addition, an unexpected dependence of the production rate on track multiplicity is observed

Socioeconomic inequalities and mortality trends in BRICS, 1990–2010

OBJECTIVE: To explore the presence and magnitude of – and change in – socioeconomic and health inequalities between and within Brazil, the Russian Federation, India, China and South Africa – the countries known as BRICS – between 1990 and 2010. METHODS: Comparable data on socioeconomic and health indicators, at both country and primary subnational levels, were obtained from publicly available sources. Health inequalities between and within countries were identified and summarized by using standard gap and gradient metrics. FINDINGS: Four of the BRICS countries showed increases in both income level and income inequality between 1990 and 2010. The exception was Brazil, where income inequality decreased over the same period. Between-country inequalities in level of education and access to sanitation remained mostly unchanged but the largest between-country difference in mean life expectancy increased, from 9 years in 1990 to 20 years in 2010. Throughout the study period, there was disproportionality in the burden of disease between BRICS. However, the national infant mortality rate fell substantially over the study period in all five countries. In Brazil and China, the magnitude of subnational income-related inequalities in infant mortality, both absolute and relative, also decreased substantially. CONCLUSION: Despite the economic prosperity and general improvements in health seen since 1990, profound inequalities in health persist both within and between BRICS. However, the substantial reductions observed – within Brazil and China – in the inequalities in income-related levels of infant mortality are encouraging

Regularity of invariant measures for a class of perturbed Ornstein-Uhlenbeck operators

In the framework of [5] we prove regularity of invariant measures #mu# for a class of Ornstein-Uhlenbeck operators perturbed by a drift which is not necessarily bounded or Lipschitz continuous. Regularity here means that #mu# is absolutely continuous with respect to the Gaussian invariant measure of the unperturbed operator with the square root of the Radon-Nikodym density in the corresponding Sobolev space of order 1. (orig.)Available from TIB Hannover: RO 5389(375) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

The puzzling MgAl anticorrelation in globular-cluster red giants: primordial plus deep mixing scenario?

Star-to-star abundance variations of C, N, O, Na and Al in globular-cluster red giants have been recently supplemented by the finding that [Mg/Fe] is depleted in stars with extremely large [Al/Fe] (Shetrone 1996a). To find out which of the magnesium isotopes is responsible for the observed depletion of [Mg/Fe] Shetrone (1996b) also undertook an isotopic analysis of Mg and found that it is &quot;2&quot;4Mg which is depleted in Al-rich giants. On the other hand, Norris and Da Costa (1995) demonstrated that even in the massive globular cluster #omega# Cen which has intrinsic spreads in both [Fe/H] and the abundances of the s-process elements, [O/Fe] anticorrelates with [Na/Fe] and [Al/Fe] as in ''normal'' monometallic clusters. These new spectroscopic results allow us to test current models of stellar evolution and nucleosynthesis, as well as those of the formation and chemical enrichment of globular clusters. In an effort to explain self-consistently these observations we have considered two possibilities: (1) a deep mixing scenario which assumes that in red giants some kind of (extra)mixing transports products of nuclear reactions from the hydrogen burning shell (HBS) to the base of the convective envelope; and (2) a combination of primordial and deep mixing scenariosAvailable from TIB Hannover: RR 4697(1039) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman