Sphingomyelinase and ceramide inhibit formation of F-actin ring in and bone resorption by rabbit mature osteoclasts

AbstractRecent studies have demonstrated that ceramide plays an important role as a second messenger in many kinds of cells. However, it is not known whether apoptosis of and bone resorption by mature osteoclasts are mediated via sphingomyelinase (SMase) and ceramide. Thus, we examined the possible involvement of SMase and ceramide in the induction of apoptosis in and bone resorption by rabbit mature osteoclasts. SMase and C2-ceramide inhibited strongly F-actin ring formation of and bone resorption by the osteoclasts. However, the osteoclast apoptosis was not induced by C2-ceramide. The ceramide inhibition of the bone resorption was suppressed by dl-threo-dihydrosphingosine, an inhibitor of sphingosine kinase. In addition, we observed that sphingosine-1-phosphate is able to inhibit bone resorption by the osteoclasts. These results suggest an important role of the sphingomyelin pathway in bone resorption by rabbit mature osteoclasts

Dengue virus type 2 unresponsive to the current PCR primer; : construction of a new PCR primer to detect all strains of Dengue virus type 2.

We found that one strain of dengue virus (Trinidad 1751; TR) did not respond to the PCR primer for Jamaica/83. We investigated such property with other 10 strains of dengue virus type 2 and found 2 more unresponsive strains. All 3 strains were isolated from the central America. To detect the envelope gene of those 3 strains by PCR, we synthesized primers based on TR strain as the reference sequence. Using these primers, we could detect the 3 strains by PCR at the usual annealing temperature. We recommed the new primer for diagnosis of DEN 2

TeV scale mirage mediation in NMSSM

We study the next-to-minimal supersymmetric standard model. We consider soft supersymmetry breaking parameters, which are induced by the mirage mediation mechanism of supersymmetry breaking. We concentrate on the mirage mediation, where the so-called mirage scale is the TeV scale. In this scenario, we can realize the up-type Higgs soft mass of O(200) GeV, while other masses such as gaugino masses and stop masses are heavy such as 1 TeV or more. Cancellation between the effective \mu-term and the down-type Higgs soft mass ameliorates the fine-tuning in the electroweak symmetry breaking even for \mu=O(500) GeV. The mixing between the doublet and singlet Higgs bosons is suppressed by (\lambda/\kappa)/tan\beta. Then the lightest doublet Higgs mass naturally reaches 125 GeV lifted by the new quartic coupling. The higgsino and singlino are light and their linear combination is the lightest superparticle.Comment: 24 pages, 24 figures, Numerical analysis is replaced with the version calculated by NMSSMTools. Comments and references are added on the suppressed doublet-singlet mixing and cases in which the 125 GeV boson is the 2nd lightest CP-even scalar. The version accepted by JHE

The PHCCEx domain of Tiam1/2 is a novel protein- and membrane-binding module

Tiam1 and Tiam2 (Tiam1/2) are guanine nucleotide-exchange factors that possess the PH–CC–Ex (pleckstrin homology, coiled coil and extra) region that mediates binding to plasma membranes and signalling proteins in the activation of Rac GTPases. Crystal structures of the PH–CC–Ex regions revealed a single globular domain, PHCCEx domain, comprising a conventional PH subdomain associated with an antiparallel coiled coil of CC subdomain and a novel three-helical globular Ex subdomain. The PH subdomain resembles the β-spectrin PH domain, suggesting non-canonical phosphatidylinositol binding. Mutational and binding studies indicated that CC and Ex subdomains form a positively charged surface for protein binding. We identified two unique acidic sequence motifs in Tiam1/2-interacting proteins for binding to PHCCEx domain, Motif-I in CD44 and ephrinB's and the NMDA receptor, and Motif-II in Par3 and JIP2. Our results suggest the molecular basis by which the Tiam1/2 PHCCEx domain facilitates dual binding to membranes and signalling proteins

Mixed Mediation of Supersymmetry Breaking with Anomalous U(1) Gauge Symmetry

Models with anomalous U(1) gauge symmetry contain various superfields which can have nonzero supersymmetry breaking auxiliary components providing the origin of soft terms in the visible sector, e.g. the U(1) vector superfield, the modulus or dilaton superfield implementing the Green-Schwarz anomaly cancellation mechanism, U(1)-charged but standard model singlet matter superfield required to cancel the Fayet-Iliopoulos term, and finally the supergravity multiplet. We examine the relative strength between these supersymmetry breaking components in a simple class of models, and find that various different mixed mediations of supersymmetry breaking, involving the modulus, gauge, anomaly and D-term mediations, can be realized depending upon the characteristics of D-flat directions and how those D-flat directions are stabilized with a vanishing cosmological constant. We identify two parameters which represent such properties and thus characterize how the various mediations are mixed. We also discuss the moduli stabilization and soft terms in a variant of KKLT scenario, in which the visible sector K\"ahler modulus is stabilized by the D-term potential of anomalous U(1) gauge symmetry.Comment: 30 pages, 5 figure

Muon anomalous magnetic moment, lepton flavor violation, and flavor changing neutral current processes in SUSY GUT with right-handed neutrino

Motivated by the large mixing angle solutions for the atmospheric and solar neutrino anomalies, flavor changing neutral current processes and lepton flavor violating processes as well as the muon anomalous magnetic moment are analyzed in the framework of SU(5) SUSY GUT with right-handed neutrino. In order to explain realistic mass relations for quarks and leptons, we take into account effects of higher dimensional operators above the GUT scale. It is shown that the supersymmetric (SUSY) contributions to the CP violation parameter in $K^0-\bar{K}^0$ mixing, $\epsilon_K$, the $\mu \to e \gamma$ branching ratio, and the muon anomalous magnetic moment become large in a wide range of parameter space. We also investigate correlations among these quantities. Within the current experimental bound of $\text{B}(\mu \to e \gamma)$, large SUSY contributions are possible either in the muon anomalous magnetic moment or in $\epsilon_K$. In the former case, the favorable value of the recent muon anomalous magnetic moment measurement at the BNL E821 experiment can be accommodated. In the latter case, the allowed region of the Kobayashi-Maskawa phase can be different from the prediction within the Standard Model (SM) and therefore the measurements of the CP asymmetry of $B\to J/\psi K_S$ mode and $\Delta m_{B_s}$ could discriminate this case from the SM. We also show that the $\tau \to \mu \gamma$ branching ratio can be close to the current experimental upperbound and the mixing induced CP asymmetry of the radiative B decay can be enhanced in the case where the neutrino parameters correspond to the Mikheyev-Smirnov-Wolfenstein small mixing angle solution.Comment: 70 pages, 14 figure

Bispectral index-guided propofol sedation during endoscopic ultrasonography

Background/Aims Bispectral index (BIS) monitors process and display electroencephalographic data are used to assess the depth of anesthesia. This study retrospectively evaluated the usefulness of BIS monitoring during endoscopic ultrasonography (EUS). Methods This study included 725 consecutive patients who underwent EUS under sedation with propofol. BIS monitoring was used in 364 patients and was not used in 361. The following parameters were evaluated: (1) median dose of propofol; (2) respiratory and circulatory depression; (3) occurrence of body movements; (4) awakening score >8 at the time; and (5) awakening score 2 hours after leaving the endoscopy room. Results The BIS group received a significantly lower median dose of propofol than the non-BIS group (159.2 mg vs. 167.5 mg; p=0.015) in all age groups. For patients aged ≥75 years, the reduction in heart rate was significantly lower in the BIS group than in the non-BIS group (1.2% vs. 9.1%; p=0.023). Moreover, the occurrence of body movements was markedly lower in the BIS group than in the non-BIS group (8.5% vs. 39.4%; p<0.001). Conclusions During EUS examination, BIS monitoring is useful for maintaining a constant depth of anesthesia, especially in patients 75 years of age or older

Aberrant Glycogen Synthase Kinase 3β Is Involved in Pancreatic Cancer Cell Invasion and Resistance to Therapy

Background and Purpose: The major obstacles to treatment of pancreatic cancer are the highly invasive capacity and resistance to chemo- and radiotherapy. Glycogen synthase kinase 3β (GSK3β) regulates multiple cellular pathways and is implicated in various diseases including cancer. Here we investigate a pathological role for GSK3β in the invasive and treatment resistant phenotype of pancreatic cancer. Methods: Pancreatic cancer cells were examined for GSK3β expression, phosphorylation and activity using Western blotting and in vitro kinase assay. The effects of GSK3β inhibition on cancer cell survival, proliferation, invasive ability and susceptibility to gemcitabine and radiation were examined following treatment with a pharmacological inhibitor or by RNA interference. Effects of GSK3β inhibition on cancer cell xenografts were also examined. Results: Pancreatic cancer cells showed higher expression and activity of GSK3β than non-neoplastic cells, which were associated with changes in its differential phosphorylation. Inhibition of GSK3β significantly reduced the proliferation and survival of cancer cells, sensitized them to gemcitabine and ionizing radiation, and attenuated their migration and invasion. These effects were associated with decreases in cyclin D1 expression and Rb phosphorylation. Inhibition of GSK3β also altered the subcellular localization of Rac1 and F-actin and the cellular microarchitecture, including lamellipodia. Coincident with these changes were the reduced secretion of matrix metalloproteinase-2 (MMP-2) and decreased phosphorylation of focal adhesion kinase (FAK). The effects of GSK3β inhibition on tumor invasion, susceptibility to gemcitabine, MMP-2 expression and FAK phosphorylation were observed in tumor xenografts. Conclusion: The targeting of GSK3β represents an effective strategy to overcome the dual challenges of invasiveness and treatment resistance in pancreatic cancer. © 2013 Kitano et al