Glial activation involvement in neuronal death by Japanese encephalitis virus infection

Japanese encephalitis is characterized by profound neuronal destruction/dysfunction and concomitant microgliosis/astrogliosis. Although substantial activation of glia is observed in Japanese encephalitis virus (JEV)-induced Japanese encephalitis, the inflammatory responses and consequences of astrocytes and microglial activation after JEV infection are not fully understood. In this study, infection of cultured neurons/glia with JEV caused neuronal death and glial activation, as evidenced by morphological transformation, increased cell proliferation and elevated tumour necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-6 and RANTES (regulated upon activation, normal T-cell expressed and secreted) production. Replication-competent JEV caused all glial responses and neurotoxicity. However, replication-incompetent JEV lost these abilities, except for the ability to change microglial morphology. The bystander damage caused by activated glia also contributed to JEV-associated neurotoxicity. Microglia underwent morphological changes, increased cell proliferation and elevated TNF-alpha, IL-1 beta, IL-6 and RANTES expression in response to JEV infection. In contrast, IL-6 and RANTES expression, but no apparent morphological changes, proliferation or TNF-alpha/IL-1 beta expression, was demonstrated in JEV-infected astrocytes. Supernatants of JEV-infected microglia, but not JEV-infected astrocytes, induced glial activation and triggered neuronal death. Antibody neutralization studies revealed that TNF-alpha and IL-1 beta, but not RANTES or IL-6, released by activated microglia appeared to play roles in JEV-associated neurotoxicity. In conclusion, following JEV infection, neuronal death was accompanied by concomitant microgliosis and astrogliosis, and neurotoxic mediators released by JEV-activated microglia, rather than by JEV-activated astrocytes, had the ability to amplify the microglial response and cause neuronal death

Measurement of the Bottom-Strange Meson Mixing Phase in the Full CDF Data Set

We report a measurement of the bottom-strange meson mixing phase \beta_s using the time evolution of B0_s -> J/\psi (->\mu+\mu-) \phi (-> K+ K-) decays in which the quark-flavor content of the bottom-strange meson is identified at production. This measurement uses the full data set of proton-antiproton collisions at sqrt(s)= 1.96 TeV collected by the Collider Detector experiment at the Fermilab Tevatron, corresponding to 9.6 fb-1 of integrated luminosity. We report confidence regions in the two-dimensional space of \beta_s and the B0_s decay-width difference \Delta\Gamma_s, and measure \beta_s in [-\pi/2, -1.51] U [-0.06, 0.30] U [1.26, \pi/2] at the 68% confidence level, in agreement with the standard model expectation. Assuming the standard model value of \beta_s, we also determine \Delta\Gamma_s = 0.068 +- 0.026 (stat) +- 0.009 (syst) ps-1 and the mean B0_s lifetime, \tau_s = 1.528 +- 0.019 (stat) +- 0.009 (syst) ps, which are consistent and competitive with determinations by other experiments.Comment: 8 pages, 2 figures, Phys. Rev. Lett 109, 171802 (2012

Free vibration analysis and design optimization of SMA/Graphite/Epoxy composite shells in thermal environments

Composite shells, which are being widely used in engineering applications, are often under thermal loads. Thermal loads usually bring thermal stresses in the structure which can significantly affect its static and dynamic behaviors. One of the possible solutions for this matter is embedding Shape Memory Alloy (SMA) wires into the structure. In the present study, thermal buckling and free vibration of laminated composite cylindrical shells reinforced by SMA wires are analyzed. Brinson model is implemented to predict the thermo-mechanical behavior of SMA wires. The natural frequencies and buckling temperatures of the structure are obtained by employing Generalized Differential Quadrature (GDQ) method. GDQ is a powerful numerical approach which can solve partial differential equations. A comparative study is carried out to show the accuracy and efficiency of the applied numerical method for both free vibration and buckling analysis of composite shells in thermal environment. A parametric study is also provided to indicate the effects of like SMA volume fraction, dependency of material properties on temperature, lay-up orientation, and pre-strain of SMA wires on the natural frequency and buckling of Shape Memory Alloy Hybrid Composite (SMAHC) cylindrical shells. Results represent the fact that SMAs can play a significant role in thermal vibration of composite shells. The second goal of present work is optimization of SMAHC cylindrical shells in order to maximize the fundamental frequency parameter at a certain temperature. To this end, an eight-layer composite shell with four SMA-reinforced layers is considered for optimization. The primary optimization variables are the values of SMA angles in the four layers. Since the optimization process is complicated and time consuming, Genetic Algorithm (GA) is performed to obtain the orientations of SMA layers to maximize the first natural frequency of structure. The optimization results show that using an optimum stacking sequence for SMAHC shells can increase the fundamental frequency of the structure by a considerable amount

FIRST SEARCHES FOR OPTICAL COUNTERPARTS TO GRAVITATIONAL-WAVE CANDIDATE EVENTS

During the LIGO and Virgo joint science runs in 2009-2010, gravitational wave (GW) data from three interferometer detectors were analyzed within minutes to select GW candidate events and infer their apparent sky positions. Target coordinates were transmitted to several telescopes for follow-up observations aimed at the detection of an associated optical transient. Images were obtained for eight such GW candidates. We present the methods used to analyze the image data as well as the transient search results. No optical transient was identified with a convincing association with any of these candidates, and none of the GW triggers showed strong evidence for being astrophysical in nature. We compare the sensitivities of these observations to several model light curves from possible sources of interest, and discuss prospects for future joint GW-optical observations of this type

Manganese modulates pro-inflammatory gene expression in activated glia

Redox-active metals are of paramount importance for biological functions. Their impact and cellular activities participate in the physiological and pathophysiological processes of the central nervous system (CNS), including inflammatory responses. Manganese is an essential trace element and it is required for normal biological activities and ubiquitous enzymatic reactions. However, excessive chronic exposure to manganese results in neurobehavioral deficits. Recent evidence suggests that manganese neurotoxicity involves activation of microglia or astrocytes, representative CNS immune cells. In this study, we assessed the molecular basis of the effects of manganese on the modulation of pro-inflammatory cytokines and nitric oxide (NO) production in primary rat cortical glial cells. Cultured glial cells consisted of 85% of astrocytes and 15% of microglia. Within the assayed concentrations, manganese was unable to induce tumor necrosis factor alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) expression, whereas it potentiated iNOS and TNF-alpha gene expression by lipopol gamma-saccharide/interferon-gamma-activated glial cells. The enhancement was accompanied by elevation of free manganese, generation of oxidative stress, activation of mitogen-activated protein kinases, and increased NF-KB and AP-1 binding activities. The potentiated degradation of inhibitory molecule IKB-alpha was one of underlying mechanisms for the increased activation of NF-KB by manganese. However, manganese decreased iNOS enzymatic activity possibly through the depletion of cofactor since exogenous tetrahydrobiopterin reversed manganese's action. These data indicate that manganese could modulate glial inflammation through variable strategies. (c) 2006 Elsevier Ltd. All rights reserved

Induction of cyclooxygenase-2 expression by manganese in cultured astrocytes

Inflammatory and oxidative events are present in neurodegenerative disorders and appear to contribute to initiation and/or progression of the disease. Within the brain, redox-active metals, such as manganese, play an important role as components of proteins essential for neural function. However, increasing evidence implies its participation in neurodegenerative diseases involving immune modulation. Prostaglandins (PGs) are lipid mediators that participate in the regulation of physiological and pathophysiological processes, particularly during brain inflammation. In this study, we investigated whether the immune modulating action of manganese involved regulation of PGE2 production in cortical astrocytes. Within nontoxic concentrations, manganese caused an elevation in the expression of cyclooxygenase-2 (COX-2) mRNA and protein and increased PGE2 release. Manganese potentiated COX-2 expression and PGE2 generation by lipopolysaccharide/interferon-gamma-activated astrocytes. The inductive action of manganese was accompanied by generation of oxidative stress, activation of mitogen-activated protein kinases (MAPKs), AKT, and protein kinase C-a (PKC-a), and increased NF-KB and AP-1 DNA binding activities. The generation of reactive oxygen species (ROS) was critical to manganese-induced changes in astrocytes, including MAPKs, PKC-a, NF-KB, AP-1, and COX-2 expression but not AKT. Collectively, these data indicate that manganese might cause changes in neural activity through the modulation of oxidative and inflammatory events in astrocytes. (C) 2006 Elsevier Ltd. All rights reserved

L-Glutamate activates RhoA GTPase leading to suppression of astrocyte stellation

The actin cytoskeleton is known to support cellular morphological changes. Rho family small GTPases function as switching molecules to promote the convergence of both extracellular and intracellular signals in regulating cytoskeletal organization. Evidence indicates that L-glutamate suppresses morphological changes of astrocytes over a broad spectrum. To test the possibility that L-glutamate affects cytoskeletal reorganization, we investigated its effect on morphological changes induced by manganese exposure. L-Glutamate concentration-dependently prevented and reversed manganese-induced astrocyte stellation and cytoskeletal disruption. The suppressive effect of L-glutamate on manganese-induced stellation was mediated by the activation of the glutamate transporter rather than ionotropic or metabotropic glutamate receptors. Pharmacological and biochemical approaches revealed the involvement of Ras homolog gene family, member A ( RhoA) activation in L-glutamate-mediated suppression of manganese-induced stellation. The activation of RhoA by L-glutamate was partly through the up-regulation of guanine nucleotide exchange factor phosphorylation and was abrogated by competitive nonsubstrate inhibitors. Furthermore, the hyperphosphorylation of myosin light chain and cofilin through the activation of RhoA following L-glutamate treatment synergistically stabilized actin stress fibres. These results suggest that manganese- induced stellation is suppressed by a mechanism involving glutamate transporters. Our in vitro findings also strongly indicate that astrocyte morphological plasticity is under the control of RhoA and that manganese and L-glutamate regulate astrocyte morphology by modulating this switching molecule under culture conditions

Effect of collagen on the mechanical properties of hydroxyapatite coatings

In this study, the mechanical properties of bioactive coatings on Ti6Al4V substrates were investigated using instrumented nanoindentation. The aim was to observe the differences in the mechanical properties before and after immersion in collagen solution. The hydroxyapatite coatings were prepared through two processes: self-assembly in simulated body fluid and a hydrothermal method. Sintered hydroxyapatite disks were used as controls. The test samples were then incubated in a dilute collagen solution for 24 hours to produce composite coatings. The materials were investigated using XRD, SEM and nanoindentation. The results showed that the grain sizes of the hydroxyapatite coatings formed using two processes were 1 mu m and 10 mu m, respectively. The Young's modulus of the pure hydroxyapatite, the disk and the coatings, was 3.6 GPa. After collagen incubation treatment, the composites had a Young's modulus of 7.5 GPa. The results also showed that the strengthening phenomena of collagen were more obvious for homogeneous and small-grain hydroxyapatite coatings. These results suggest that there are similarities between these HAp/collagen composited and natural composite materials, such as teeth and bones. (C) 2011 Elsevier Ltd. All rights reserved

Opioids modulate post-ischemic progression in a rat model of stroke

Alterations in the opioidergic system have been found in cerebral ischemia. Neuroprotection studies have demonstrated the involvement of the opioidergic system in cerebral ischemia/reperfusion (I/R). However, the neuroprotective mechanisms remain largely unclear. This study was conducted to investigate whether intracerebroventricular administration of opioidergic agonists; has a neuroprotective effect against cerebral ischemia in rats and, if this proved to be the case, to determine the potential neuroprotective mechanisms. Using a focal cerebral I/R. rat model, we demonstrated that the opioidergic agents, BW373U86 (delta agonist) and Dynorphin A 1-13 (kappa agonist), but not TAPP (mu agonist), attenuated cerebral ischemic injury as manifested in the reduction of cerebral infarction and preservation of neurons. The antagonism assay showed that the neuroprotective effect of Dynorphin A was attenuated by nor-Binaltorphimine (kappa antagonist). Surprisingly, BW373U86-induced neuroprotection was not changed by Naltrindole (delta antagonist). These findings indicate that BW373U86 and Dynorphin A exerted distinct neuroprotection against ischemia via opioid-independent and -dependent mechanisms, respectively. The post-ischemic protection in beneficial treatments was accompanied by alleviations in brain edema, inflammatory cell infiltration, and pro-inflaminatory cytokine interleukin 6 (IL-6) expression. In vitro cell study further demonstrated that the opioidergic agonists, delta and kappa, but not mu, attenuated IL-6 production from stimulated glial cells. Our findings indicate that opioidergic agents have a role in post-ischemic progression through both opioid-dependent and -independent mechanisms. In spite of the distinct-involved action mechanism, the potential neuroprotective effect of opioidergic compounds was associated with immune suppression. Taken together, these findings suggest a potential role for opioidergic agents in the therapeutic consideration of neuroinflammatory diseases. However, a better understanding of the mechanisms involved is necessary before this therapeutic potential can be realized. (C) 2008 Elsevier Ltd. All rights reserved

Stearic acid attenuates cholestasis-induced liver injury

Inflammation is involved in cholestasis-induced hepatic damage. Stearic acid has been shown to possess anti-inflammatory potential. We assessed whether stearic acid has protective effects against cholestasis-related liver damage. Cholestasis was produced by bile duct ligation (BDL) in male Sprague-Dawley rats for 3 weeks. Daily administration of stearic acid was started 2 weeks before injury and lasted for 5 weeks. In comparison with the control group, the BDL group showed hepatic damage as evidenced by elevation in serum biochemicals, ductular reaction, fibrosis, and inflammation. These pathophysiological changes were attenuated by chronic stearic acid Supplementation. The anti-fibrotic effect of stearic acid was accompanied by reductions in alpha-smooth muscle actin-positive matrix-producing cells and critical fibrogenic cytokine transforming growth factor beta-1 production. Stearic acid also attenuated BDL-induced leukocyte accumulation and NF-kappa B activation. The data indicate that Stearic acid attenuates BDL-induced cholestatic liver injury. The hepatoprotective effect of stearic acid is associated with anti-inflammatory potential. (c) 2009 Elsevier Inc. All rights reserved