Phosphocholine-Modified Lipooligosaccharides of Haemophilus influenzae Inhibit ATP-Induced IL-1beta Release by Pulmonary Epithelial Cells

Phosphocholine-modified bacterial cell wall components are virulence factors enabling immune evasion and permanent colonization of the mammalian host, by mechanisms that are poorly understood. Recently, we demonstrated that free phosphocholine (PC) and PC-modified lipooligosaccharides (PC-LOS) from Haemophilus influenzae, an opportunistic pathogen of the upper and lower airways, function as unconventional nicotinic agonists and efficiently inhibit the ATP-induced release of monocytic IL-1beta. We hypothesize that H. influenzae PC-LOS exert similar effects on pulmonary epithelial cells and on the complex lung tissue. The human lung carcinoma-derived epithelial cell lines A549 and Calu-3 were primed with lipopolysaccharide from Escherichia coli followed by stimulation with ATP in the presence or absence of PC or PC-LOS or LOS devoid of PC. The involvement of nicotinic acetylcholine receptors was tested using specific antagonists. We demonstrate that PC and PC-LOS efficiently inhibit ATP-mediated IL-1beta release by A549 and Calu-3 cells via nicotinic acetylcholine receptors containing subunits alpha7, alpha9, and/or alpha10. Primed precision-cut lung slices behaved similarly. We conclude that H. influenzae hijacked an endogenous anti-inflammatory cholinergic control mechanism of the lung to evade innate immune responses of the host. These findings may pave the way towards a host-centered antibiotic treatment of chronic airway infections with H. influenzae

Bergbaubedingte Schwermetallbelastungen von Böden und Nutzpflanzen in einem Bewässerungsgebiet - Ausmaß und ökologische Bedeutung -

Durch Abspülung von Abraumhalden einer Edelmetallmine südlich von Tbilisi in Georgien wird der Fluss Mashavera stark mit extrem schwermetallhaltigen (Kupfer, Zink, Cadmium) Schwebstoffen befrachtet. Das Wasser des Mashavera wird über mehrere Kanäle in das Bewässerungssystem des Mashavera-Tals und des Poladauri-Tals eingespeist und gelangt per Furchenbewässerung auf die unterhalb des Kanalsystems gelegenen, landwirtschaftlich genutzten Flächen. Auf Grund der seit Jahrzehnten anhaltenden Kontamination des Bewässerungswassers wurden die bewässerten Böden des Mashavera-Tals und des Poladauri-Tals großflächig mit Schwermetallen belastet. Im Rahmen eines dreijährigen Forschungsvorhabens wurde die Art, die Verbreitung und das Ausmaß der Schwermetallbelastung, sowie ihre ökotoxikologische Bedeutung für die Nahrungskette im System Boden-Pflanze eines kontinentalen Klimaraums untersucht. Die Ergebnisse der Arbeit zeigen, dass für Oberböden des Untersuchungsgebietes eine großräumige, gravierende Belastungssituation mit Schwermetallen vorliegt. Die Schwermetallgesamtgehalte der Oberböden werden im Wesentlichen durch die Nutzungsart des Standortes und durch das Relief bestimmt. Die Flächen, die am längsten und intensivsten mit belastetem Wasser bewässert worden sind, weisen Konzentrationen bis 3.000 mg*kg-1 Cu, 2.500 mg*kg-1 Zn und 17 mg*kg-1 Cd auf. Die Belastungssituation nimmt hierbei generell zu in der Reihenfolge: (1) ackerbaulich genutzte Flächen, (2) zum Gemüseanbau genutzte Hausgärten und (3) zum Wein- und Obstanbau genutzte Böden. Die im neutralen bis schwach alkalischen Bereich liegenden pH-Werte der Oberböden bewirken zusammen mit den Gehalten an Carbonaten, organischer Substanz, Ton und Metalloxiden eine weitestgehende Immobilisierung der Schwermetalle. Trotz hoher Gesamtgehalte liegen daher nur geringe Anteile der Schwermetalle in der mobilen, NH4NO3-extrahierbaren Fraktion vor. Diese betragen für Cu und Zn weniger als 1 % der Gesamtgehalte und erreichen im Falle von Cd maximal 1,5 % der Gesamtgehalte. Allerdings werden bei hohen Cd-Gesamtgehalten auch die NH4NO3-extrahierbaren, d.h. mobilen Anteile zu einer ökotoxikologisch relevanten Größe. In Gefäß- und Feldversuchen wurde mit ausgewählten Böden des Untersuchungsgebietes der Schwermetalltransfer in Nutzpflanzen untersucht. Trotz niedriger NH4NO3- extrahierbarer Schwermetallgehalte wurde über die Pflanzenaufnahme eine deutliche Überschreitung der Toleranzschwelle des menschlichen Organismus für Cd festgestellt. IX Wir gehen davon aus, dass die Schwermetallanreicherungen in den Pflanzen im Untersuchungsgebiet wesentlich höher liegen müssen, als dies auf Grund der vorliegenden bodenanalytischen Daten zu erwarten wäre. Insbesondere für die Bewertung der Bioverfügbarkeit von Cd scheint die NH4NO3-Methode auf alkalischen Böden nicht geeignet zu sein. Das Untersuchungsgebiet ist die Region, in der Frischgemüse sowohl für die Selbstversorgung der örtlichen Bevölkerung als auch für die Millionenmetropole Tiflis/Tbilisi produziert wird. Es ist damit zu rechnen, dass das Ausmaß der Kontamination infolge der intensiven Bewässerung sehr stark und kontinuierlich ansteigen wird. Es ist daher zwingend erforderlich, für das Untersuchungsgebiet Handlungsstategien zu erarbeiten, um die Umweltkompartimente Boden und Wasser langfristig zu schützen und zu sanieren und um den Transfer von Schwermetallen in die Nahrungskette zu unterbinden. --

Characterization of the state of dispersion of carbon nanotubes in polymer nanocomposites

A practical overview of possibilities and limits to characterize the state of dispersion of carbon nanotubes (CNT) in polymer based nanocomposites is given. The most important and widely available methods are discussed with practical employment in mind. One focus is the quantitative characterization of the state of dispersion in solid samples using microscopy techniques such as optical microscopy or transmission electron microscopy. For dispersions of CNTs in aqueous media, solvents or monomers a sedimentation analysis is presented. This way dispersability and dispersion state of CNTs can be assessed. Indirect methods such as electrical conductivity measurements and rheological tests, dynamic differential scanning calorimetry and mechanical test are discussed. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Inhibition of heat shock protein 90 with AUY922 represses tumor growth in a transgenic mouse model of islet cell neoplasms

Background: This study was designed to evaluate the role of heat shock protein 90 (HSP90) in tumor progression of murine islet cell tumors. Blockade of HSP90 has recently been proposed as a therapeutic target, but effects in models of islet cell tumors with AUY922, a newly developed HSP90 inhibitor, have not been examined. Material and Methods: The carcinoid cell line BON-1 and the HSP90 inhibitor AUY922 were used to determine effects on signaling and growth in vitro. In vivo transgenic RIP1-Tag2 mice, which develop islet cell neoplasms, were treated with vehicle or AUY922 (25 mg/kg/twice per week) from week 5 until death. The resected pancreata were evaluated macroscopically and microscopically by immunohistochemistry. Quantitative real-time PCR was performed for HSP90 targets with RNA from islets isolated from treated and untreated RIP1-Tag2 mice. Results: HSP90 blockade impaired constitutive and growth factor-induced signaling in vitro. Moreover, HSP90 inhibition attenuated in vitro cell growth in a dose-dependent manner. In vivo, AUY922 significantly reduced tumor volume by 92% compared to untreated controls (p = 0.000), and median survival in the used transgenic mouse model was prolonged (110 vs. 119 days; p = 0.75). Quantitative real-time PCR for downstream target genes of HSP90 demonstrated significant downregulation in the islet cell tumors of RIP1-Tag2 mice treated with AUY922, confirming our ability to achieve effective pharmacologic levels of AUY922 within the desired tissue site in vivo. Conclusion: This is the first study to show that the HSP90 antagonist AUY922 may provide a new option for therapy of islet cell neoplasms

Absence of chronic hepatitis E in a German cohort of common variable immunodeficiency patients

Cases of chronic or prolonged hepatitis E virus (HEV) infections have been described in solid organ transplant recipients, HIV infected patients and in patients with malignancies or idiopathic CD4+ T lymphopenia. It is unknown if HEV infection also takes chronic courses in patients with common variable immunodeficiency (CVID). We studied a cohort of 73 CVID patients recruited in a low endemic Central European country. None of the subjects tested positive for HEV RNA or anti-HEV IgG. Immunoglobulin transfusions (n=10) tested negative for HEV RNA but all were anti-HEV positive. To verify that such pooled blood products contain anti-HEV protective antibodies we measured the anti-HEV IgG optical density (OD) values in patients before and after transfusion. Anti-HEV OD values increased after infusion but did not reach the cut-off considered as positive. Thus, chronic HEV infections seem to be rare events in CVID patients in Germany. Commercially available immuno globulin infusions contain anti HEV antibodies and may contribute to protection from HEV infectio

Superconducting undulator activities at the European X-ray Free-Electron Laser Facility

For more than 5 years, superconducting undulators (SCUs) have been successfully delivering X-rays in storage rings. The European X-Ray Free-Electron Laser Facility (XFEL) plans to demonstrate the operation of SCUs in X-ray free-electron lasers (FELs). For the same geometry, SCUs can reach a higher peak field on the axis with respect to all other available technologies, offering a larger photon energy tunability range. The application of short-period SCUs in a high electron beam energy FEL > 11 GeV will enable lasing at very hard X-rays > 40 keV. The large tunability range of SCUs will allow covering the complete photon energy range of the soft X-ray experiments at the European XFEL without changing electron beam energy, as currently needed with the installed permanent magnet undulators. For a possible continuous-wave (CW) upgrade under discussion at the European XFEL with a lower electron beam energy of approximately 7–8 GeV, SCUs can provide the same photon energy range as available at present with the permanent magnet undulators and electron energies. This paper will describe the potential of SCUs for X-ray FELs. In particular, it will focus on the different activities ongoing at the European XFEL and in collaboration with DESY to allow the implementation of SCUs in the European XFEL in the upcoming years

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Meta-Analysis of 28,141 Individuals Identifies Common Variants within Five New Loci That Influence Uric Acid Concentrations

Elevated serum uric acid levels cause gout and are a risk factor for cardiovascular disease and diabetes. To investigate the polygenetic basis of serum uric acid levels, we conducted a meta-analysis of genome-wide association scans from 14 studies totalling 28,141 participants of European descent, resulting in identification of 954 SNPs distributed across nine loci that exceeded the threshold of genome-wide significance, five of which are novel. Overall, the common variants associated with serum uric acid levels fall in the following nine regions: SLC2A9 (p = 5.2×10−201), ABCG2 (p = 3.1×10−26), SLC17A1 (p = 3.0×10−14), SLC22A11 (p = 6.7×10−14), SLC22A12 (p = 2.0×10−9), SLC16A9 (p = 1.1×10−8), GCKR (p = 1.4×10−9), LRRC16A (p = 8.5×10−9), and near PDZK1 (p = 2.7×10−9). Identified variants were analyzed for gender differences. We found that the minor allele for rs734553 in SLC2A9 has greater influence in lowering uric acid levels in women and the minor allele of rs2231142 in ABCG2 elevates uric acid levels more strongly in men compared to women. To further characterize the identified variants, we analyzed their association with a panel of metabolites. rs12356193 within SLC16A9 was associated with DL-carnitine (p = 4.0×10−26) and propionyl-L-carnitine (p = 5.0×10−8) concentrations, which in turn were associated with serum UA levels (p = 1.4×10−57 and p = 8.1×10−54, respectively), forming a triangle between SNP, metabolites, and UA levels. Taken together, these associations highlight additional pathways that are important in the regulation of serum uric acid levels and point toward novel potential targets for pharmacological intervention to prevent or treat hyperuricemia. In addition, these findings strongly support the hypothesis that transport proteins are key in regulating serum uric acid levels

Genome-wide Association Study of Alcohol Dependence

Identification of genes contributing to alcohol dependence will improve our understanding of the mechanisms underlying this disorder