IMMUNOMODULATORS IN PULMOLOGIGAL PRACTICE

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Building block libraries and structural considerations in the self-assembly of polyoxometalate and polyoxothiometalate systems

Inorganic metal-oxide clusters form a class of compounds that are unique in their topological and electronic versatility and are becoming increasingly more important in a variety of applications. Namely, Polyoxometalates (POMs) have shown an unmatched range of physical properties and the ability to form structures that can bridge several length scales. The formation of these molecular clusters is often ambiguous and is governed by self-assembly processes that limit our ability to rationally design such molecules. However, recent years have shown that by considering new building block principles the design and discovery of novel complex clusters is aiding our understanding of this process. Now with current progress in thiometalate chemistry, specifically polyoxothiometalates (POTM), the field of inorganic molecular clusters has further diversified allowing for the targeted development of molecules with specific functionality. This chapter discusses the main differences between POM and POTM systems and how this affects synthetic methodologies and reactivities. We will illustrate how careful structural considerations can lead to the generation of novel building blocks and further deepen our understanding of complex systems

In-medium ω\omega mass from the γ+Nb→π0γ+X\gamma + Nb \to \pi^{0}\gamma + X reaction

Data on the photoproduction of $\omega$ mesons on nuclei have been re-analyzed in a search for in-medium modifications. The data were taken with the Crystal Barrel(CB)/TAPS detector system at the ELSA accelerator facility in Bonn. First results from the analysis of the data set were published by D. Trnka et al. in Phys. Rev. Lett 94 (2005) 192303 \cite{david}, claiming a lowering of the $\omega$ mass in the nuclear medium by 14$$ at normal nuclear matter density. The extracted $\omega$ line shape was found to be sensitive to the background subtraction. For this reason a re-analysis of the same data set has been initiated and a new method has been developed to reduce the background and to determine the shape and absolute magnitude of the background directly from the data. Details of the re-analysis and of the background determination are described. The $\omega$ signal on the $Nb$ target, extracted in the re-analysis, does not show a deviation from the corresponding line shape on a $LH_2$ target, measured as reference. The earlier claim of an in-medium mass shift is thus not confirmed. The sensitivity of the $\omega$ line shape to different in-medium modification scenarios is discussed.Comment: 13 pages and 11 figures, submitted for publicatio

Modification of the ω\omega-Meson Lifetime in Nuclear Matter

The photo production of $\omega$ mesons on the nuclei C, Ca, Nb and Pb has been measured using the Crystal Barrel/TAPS detector at the ELSA tagged photon facility in Bonn. The dependence of the $\omega$ meson cross section on the nuclear mass number has been compared with three different types of models, a Glauber analysis, a BUU analysis of the Giessen theory group and a calculation by the Valencia theory group. In all three cases, the inelastic $\omega$ width is found to be $130-150 \rm{MeV/c^2}$ at normal nuclear matter density for an average 3-momentum of 1.1 GeV/c. In the restframe of the $\omega$ meson, this inelastic $\omega$ width corresponds to a reduction of the $\omega$ lifetime by a factor $\approx 30$. For the first time, the momentum dependent $\omega$N cross section has been extracted from the experiment and is in the range of 70 mb.Comment: 5 pages, 4 figure

Quasi-free photoproduction of eta-mesons of the neutron

Quasi-free photoproduction of eta-mesons off nucleons bound in the deuteron has been measured with the CBELSA/TAPS detector for incident photon energies up to 2.5 GeV at the Bonn ELSA accelerator. The eta-mesons have been detected in coincidence with recoil protons and recoil neutrons, which allows a detailed comparison of the quasi-free n(gamma,eta)n and p(gamma,eta)p reactions. The excitation function for eta-production off the neutron shows a pronounced bump-like structure at W=1.68 GeV (E_g ~ 1 GeV), which is absent for the proton.Comment: accepted for publication in Phys. Rev. Let

K^0 pi^0 Sigma^+ and K^*0 Sigma^+ photoproduction off the proton

The exclusive reactions $\gamma p \to K^{*0} \Sigma^+(1189)$ and $\gamma p \to K^{0} \pi^{0}\Sigma^+(1189)$, leading to the p 4$\pi^{0}$ final state, have been measured with a tagged photon beam for incident energies from threshold up to 2.5 GeV. The experiment has been performed at the tagged photon facility of the ELSA accelerator (Bonn). The Crystal Barrel and TAPS detectors were combined to a photon detector system of almost 4$\pi$ geometrical acceptance. Differential and total cross sections are reported. At energies close to the threshold, a flat angular distribution has been observed for the reaction $\gamma p\to K^{0} \pi^{0}\Sigma^+$ suggesting dominant s-channel production. $\Sigma^*(1385)$ and higher lying hyperon states have been observed. An enhancement in the forward direction in the angular distributions of the reaction $\gamma p \to K^{*0}\Sigma^+$ indicates a $t$-channel exchange contribution to the reaction mechanism. The experimental data are in reasonable agreement with recent theoretical predictions.Comment: 11 pages, 13 figures, submitted to EPJ

Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors

Fluorescent D-amino-acids reveal bi-cellular cell wall modifications important for Bdellovibrio bacteriovorous predation

Modification of essential bacterial peptidoglycan (PG) containing cell walls can lead to antibiotic resistance, for example β-lactam resistance by L,D-transpeptidase activities. Predatory Bdellovibrio bacteriovorus are naturally antibacterial and combat infections by traversing, modifying and finally destroying walls of Gram-negative prey bacteria, modifying their own PG as they grow inside prey. Historically, these multi-enzymatic processes on two similar PG walls have proved challenging to elucidate. Here, with a PG labelling approach utilizing timed pulses of multiple fluorescent D-amino acids (FDAAs), we illuminate dynamic changes that predator and prey walls go through during the different phases of bacteria:bacteria invasion. We show formation of a reinforced circular port-hole in the prey wall; L,D-transpeptidaseBd mediated D-amino acid modifications strengthening prey PG during Bdellovibrio invasion and a zonal mode of predator-elongation. This process is followed by unconventional, multi-point and synchronous septation of the intracellular Bdellovibrio, accommodating odd- and even-numbered progeny formation by non-binary division

Epigenetic Silencing of Host Cell Defense Genes Enhances Intracellular Survival of the Rickettsial Pathogen Anaplasma phagocytophilum

Intracellular bacteria have evolved mechanisms that promote survival within hostile host environments, often resulting in functional dysregulation and disease. Using the Anaplasma phagocytophilum–infected granulocyte model, we establish a link between host chromatin modifications, defense gene transcription and intracellular bacterial infection. Infection of THP-1 cells with A. phagocytophilum led to silencing of host defense gene expression. Histone deacetylase 1 (HDAC1) expression, activity and binding to the defense gene promoters significantly increased during infection, which resulted in decreased histone H3 acetylation in infected cells. HDAC1 overexpression enhanced infection, whereas pharmacologic and siRNA HDAC1 inhibition significantly decreased bacterial load. HDAC2 does not seem to be involved, since HDAC2 silencing by siRNA had no effect on A. phagocytophilum intracellular propagation. These data indicate that HDAC up-regulation and epigenetic silencing of host cell defense genes is required for A. phagocytophilum infection. Bacterial epigenetic regulation of host cell gene transcription could be a general mechanism that enhances intracellular pathogen survival while altering cell function and promoting disease

Kaposi's Sarcoma Herpesvirus Upregulates Aurora A Expression to Promote p53 Phosphorylation and Ubiquitylation

Aberrant expression of Aurora A kinase has been frequently implicated in many cancers and contributes to chromosome instability and phosphorylation-mediated ubiquitylation and degradation of p53 for tumorigenesis. Previous studies showed that p53 is degraded by Kaposi's sarcoma herpesvirus (KSHV) encoded latency-associated nuclear antigen (LANA) through its SOCS-box (suppressor of cytokine signaling, LANASOCS) motif-mediated recruitment of the EC5S ubiquitin complex. Here we demonstrate that Aurora A transcriptional expression is upregulated by LANA and markedly elevated in both Kaposi's sarcoma tissue and human primary cells infected with KSHV. Moreover, reintroduction of Aurora A dramatically enhances the binding affinity of p53 with LANA and LANASOCS-mediated ubiquitylation of p53 which requires phosphorylation on Ser215 and Ser315. Small hairpin RNA or a dominant negative mutant of Aurora A kinase efficiently disrupts LANA-induced p53 ubiquitylation and degradation, and leads to induction of p53 transcriptional and apoptotic activities. These studies provide new insights into the mechanisms by which LANA can upregulate expression of a cellular oncogene and simultaneously destabilize the activities of the p53 tumor suppressor in KSHV-associated human cancers