Legionella pneumophila infection induces programmed cell death, caspase activation, and release of high-mobility group box 1 protein in A549 alveolar epithelial cells: inhibition by methyl prednisolone

<p>Abstract</p> <p>Background</p> <p><it>Legionella pneumophila </it>pneumonia often exacerbates acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Apoptosis of alveolar epithelial cells is considered to play an important role in the pathogenesis of ALI and ARDS. In this study, we investigated the precise mechanism by which A549 alveolar epithelial cells induced by <it>L. pneumophila </it>undergo apoptosis. We also studied the effect of methyl prednisolone on apoptosis in these cells.</p> <p>Methods</p> <p>Nuclear deoxyribonucleic acid (DNA) fragmentation and caspase activation in <it>L. pneumophila</it>-infected A549 alveolar epithelial cells were assessed using the terminal deoxyribonucleotidyl transferase-mediated triphosphate (dUTP)-biotin nick end labeling method (TUNEL method) and colorimetric caspase activity assays. The virulent <it>L. pneumophila </it>strain AA100jm and the avirulent <it>dotO </it>mutant were used and compared in this study. In addition, we investigated whether methyl prednisolone has any influence on nuclear DNA fragmentation and caspase activation in A549 alveolar epithelial cells infected with <it>L. pneumophila</it>.</p> <p>Results</p> <p>The virulent strain of <it>L. pneumophila </it>grew within A549 alveolar epithelial cells and induced subsequent cell death in a dose-dependent manner. The avirulent strain <it>dotO </it>mutant showed no such effect. The virulent strains of <it>L. pneumophila </it>induced DNA fragmentation (shown by TUNEL staining) and activation of caspases 3, 8, 9, and 1 in A549 cells, while the avirulent strain did not. High-mobility group box 1 (HMGB1) protein was released from A549 cells infected with virulent <it>Legionella</it>. Methyl prednisolone (53.4 μM) did not influence the intracellular growth of <it>L. pneumophila </it>within alveolar epithelial cells, but affected DNA fragmentation and caspase activation of infected A549 cells.</p> <p>Conclusion</p> <p>Infection of A549 alveolar epithelial cells with <it>L. pneumophila </it>caused programmed cell death, activation of various caspases, and release of HMGB1. The dot/icm system, a major virulence factor of <it>L. pneumophila</it>, is involved in the effects we measured in alveolar epithelial cells. Methyl prednisolone may modulate the interaction of <it>Legionella </it>and these cells.</p

Impulse Control in Finance: Numerical Methods and Viscosity Solutions

The goal of this thesis is to provide efficient and provably convergent numerical methods for solving partial differential equations (PDEs) coming from impulse control problems motivated by finance. Impulses, which are controlled jumps in a stochastic process, are used to model realistic features in financial problems which cannot be captured by ordinary stochastic controls. The dynamic programming equations associated with impulse control problems are Hamilton-Jacobi-Bellman quasi-variational inequalities (HJBQVIs) Other than in certain special cases, the numerical schemes that come from the discretization of HJBQVIs take the form of complicated nonlinear matrix equations also known as Bellman problems. We prove that a policy iteration algorithm can be used to compute their solutions. In order to do so, we employ the theory of weakly chained diagonally dominant (w.c.d.d.) matrices. As a byproduct of our analysis, we obtain some new results regarding a particular family of Markov decision processes which can be thought of as impulse control problems on a discrete state space and the relationship between w.c.d.d. matrices and M-matrices. Since HJBQVIs are nonlocal PDEs, we are unable to directly use the seminal result of Barles and Souganidis (concerning the convergence of monotone, stable, and consistent numerical schemes to the viscosity solution) to prove the convergence of our schemes. We address this issue by extending the work of Barles and Souganidis to nonlocal PDEs in a manner general enough to apply to HJBQVIs. We apply our schemes to compute the solutions of various classical problems from finance concerning optimal control of the exchange rate, optimal consumption with fixed and proportional transaction costs, and guaranteed minimum withdrawal benefits in variable annuities

Solitary Peutz-Jeghers type hamartomatous polyps in the duodenum are not always associated with a low risk of cancer: two case reports

INTRODUCTION: A hamartomatous polyp without associated mucocutaneous pigmentation or a family history of Peutz-Jeghers Syndrome is diagnosed as a solitary Peutz-Jeghers type hamartomatous polyp. As compared with Peutz-Jeghers Syndrome, Peutz-Jeghers type hamartomatous polyps are diagnosed with a lower risk of cancer and are regarded as a different disorder. CASE PRESENTATION: In case one, we describe an 84-year-old Japanese man with a 14 mm duodenal polyp. Endoscopic mucosal resection was performed and histological examination showed findings suggestive of a hamartomatous polyp with a focus of well-differentiated adenocarcinoma. In case two, we describe a 76-year-old Japanese man who had been treated for prostate, rectal and lung cancer. Upper gastrointestinal endoscopy revealed a duodenal polyp measuring 15 mm in diameter. Endoscopic mucosal resection was performed, and histological examination showed findings suggestive of a hamartomatous polyp. Liver and thyroid cancers were found after the endoscopic treatment. CONCLUSION: Although duodenal solitary hamartomatous polyps are associated with a lower risk of cancer, four patients, including our cases, have been diagnosed with cancerous polyps. Patients with duodenal solitary hamartomatous polyps should be treated by endoscopic or surgical resection and need whole-body screening

Heterologous expression and characterization of CpI, OcpA, and novel serine-type carboxypeptidase OcpB from Aspergillus oryzae

In the genome of Aspergillus oryzae, 12 genes have been predicted to encode serine-type carboxypeptidases. However, the carboxypeptidase activities of the proteins encoded by these genes have not yet been confirmed experimentally. In this study, we have constructed three of these 12 genes overexpressing strains using Aspergillus nidulans and characterized their overproduced recombinant proteins. Of these three genes, one was previously named cpI; the other two have not been reported yet, and hence, we named them ocpA and ocpB. The recombinant proteins released amino acid residues from the C terminus of peptides, and the activity of the enzymes was inhibited by phenylmethylsulfonyl fluoride, indicating the enzymes to be serine-type carboxypeptidases. Recombinant OcpA, OcpB, and CpI were stable at 45°C, 55°C, and 55°C, respectively, at a low pH. The enzymatic properties of recombinant OcpB were different from those of any reported serine-type carboxypeptidase. On the other hand, recombinant OcpA had similar enzymatic properties to A. oryzae carboxypeptidases O1 and O2. The DNA and N-terminal amino acid sequences of carboxypeptidases O1 and O2 from A. oryzae IAM2640 were similar to those of OcpA. Result of transcriptional analysis of ocpA, ocpB, and cpI suggest differences in transcriptional regulation between these genes

Common Variants in MAGI2 Gene Are Associated with Increased Risk for Cognitive Impairment in Schizophrenic Patients

Schizophrenia is a complex psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive impairment. MAGI2, a relatively large gene (∼1.5 Mbps) that maps to chromosome 7q21, is involved in recruitment of neurotransmitter receptors such as AMPA- and NMDA-type glutamate receptors. A genetic association study designed to evaluate the association between MAGI2 and cognitive performance or schizophrenia has not been conducted. In this case-control study, we examined the relationship of single nucleotide polymorphism (SNP) variations in MAGI2 and risk for schizophrenia in a large Japanese sample and explored the potential relationships between variations in MAGI2 and aspects of human cognitive function related to glutamate activity. Based on the result of first schizophrenia genome-wide association study in a Japanese population (JGWAS), we selected four independent SNPs and performed an association study using a large independent Japanese sample set (cases 1624, controls 1621). Wisconsin Card Sorting Test (WCST) was used to evaluate executive function in 114 cases and 91 controls. We found suggestive evidence for genetic association of common SNPs within MAGI2 locus and schizophrenia in Japanese population. Furthermore in terms of association between MAGI2 and cognitive performance, we observed that genotype effect of rs2190665 on WCST score was significant (p = 0.034) and rs4729938 trended toward significance (p = 0.08). In conclusion, although we could not detect strong genetic evidence for association of common variants in MAGI2 and increased schizophrenia risk in a Japanese population, these SNPs may increase risk of cognitive impairment in schizophrenic patients

Biosynthesis of Guanidinoacetic Acid in Isolated Renal Tubules

Peer Reviewe

Experimental Formation and Mechanism Study for Super-High Dielectric Constant AlO_x/TiO_y Nanolaminates

Super-high dielectric constant (k) AlOx/TiOy nanolaminates (ATO NLs) are deposited by an atomic layer deposition technique for application in next-generation electronics. Individual multilayers with uniform thicknesses are formed for the ATO NLs. With an increase in AlOx content in each ATO sublayer, the shape of the Raman spectrum has a tendency to approach that of a single AlOx layer. The effects of ATO NL deposition conditions on the electrical properties of the metal/ATO NL/metal capacitors were investigated. A lower deposition temperature, thicker ATO NL, and lower TiOy content in each ATO sublayer can lead to a lower leakage current and smaller loss tangent at 1 kHz for the capacitors. A higher deposition temperature, larger number of ATO interfaces, and higher TiOy content in each ATO sublayer are important for obtaining higher k values for the ATO NLs. With an increase in resistance in the capacitors, the ATO NLs vary from semiconductors to insulators and their k values have a tendency to decrease. For most of the capacitors, the capacitances reduce with increments in absolute measurement voltage. There are semi-circular shapes for the impedance spectra of the capacitors. By fitting them with the equivalent circuit, it is observed that with the increase in absolute voltage, both parallel resistance and capacitance decrease. The variation in the capacitance is explained well by a novel double-Schottky electrode contact model. The formation of super-high k values for the semiconducting ATO NLs is possibly attributed to the accumulation of charges