Abstract Previous data demonstrate that traumatic brain injury (TBI) activates autophagy, and increases microtubule-associated protein 1 light chain 3 (LC3) immunostaining mainly in neurons. However, ...the role of autophagy in traumatic brain damage remains elusive. The aim of the present study was to investigate the autophagic mechanisms participating in traumatic brain injury. The autophagy inhibitors 3-methyladenine (3-MA) and bafliomycin A1 (BFA) were administered with a single i.c.v. injection before TBI. We first examined the protein levels of Beclin-1 and LC3 II, which have been found to promote autophagy previously. Immunoblotting analysis showed that 3-MA pretreatment reduced post-TBI Beclin-1 and LC3-II levels, and maintained p62/SQSTM1 (p62) levels. In addition, double immunolabeling showed that the increased punctate LC3-II dots colocalizing with Propidium Iodide (PI)-stained nuclei at 24 h after injury, were partially inhibited by 3-MA pretreatment. Furthermore, inhibition of autophagy could reduce TBI-induced cell injury assessed with i.p. injection of PI and lesion volume, and attenuate behavioral outcome evaluated by motor test and Morris water maze. The neuroprotective effects were associated with an inhibition on TBI-induced up-regulation of LC3, Beclin-1, cathepsin B, caspase-3 and the Beclin-1/Bcl-2 ratio. Taken together, these data imply that the autophagy pathway is involved in the pathophysiologic responses after TBI, and inhibition of this pathway may help attenuate traumatic damage and functional outcome deficits.
Ultrathin FeO(1
1
1) films grown on Pt(1
1
1) unexpectedly showed high activity towards CO oxidation. The reaction proceeds through the formation of a well-ordered, oxygen-rich FeO
x
(1
<
x
<
2) ...film. In CO-rich ambient the film dewets the Pt surface, ultimately resulting in highly dispersed iron oxide particles on Pt(1
1
1).
CO oxidation on a clean Pt(1
1
1) single crystal and thin iron oxide films grown on Pt(1
1
1) was studied at different CO:O
2 ratios (between 1:5 and 5:1) and partial pressures up to 60
mbar at 400–450
K. Structural characterization of the model catalysts was performed by scanning tunnelling microscopy, low energy electron diffraction, Auger electron spectroscopy and temperature-programmed desorption. It was found that monolayer FeO(1
1
1) films grown on Pt(1
1
1) were much more active than clean Pt(1
1
1) and nm-thick Fe
3O
4(1
1
1) films at all reaction conditions studied. Post-characterization of the catalysts revealed that at CO:O
2
>
1 the FeO(1
1
1) film dewets the Pt surface with time, ultimately resulting in highly dispersed iron oxide particles on Pt(1
1
1). The film dewetting was monitored
in situ by polarization-modulated infrared reflection absorption spectroscopy. The reaction rate at 450
K exhibited first order for O
2 and non-monotonously depended on CO pressure. In O
2-rich ambient the films were enriched with oxygen while maintaining the long-range ordering. Based on the structure-reactivity relationships observed for the FeO/Pt films, we propose that the reaction proceeds through the formation of a well-ordered, oxygen-rich FeO
x
(1
<
x
<
2) film that reacts with CO through the redox mechanism. The reaction-induced dewetting in fact deactivates the catalyst. The results may aid in our deeper understanding of reactivity of metal particles encapsulated by thin oxide films as a result of strong metal–support interaction.
Abstract Previous studies have demonstrated that pioglitazone (Piog), a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, inhibits ischemia-induced brain injury. Piog has also been ...shown to exert anti-inflammatory effects by attenuation of nuclear factor-κB (NF-κB) activation after myocardial ischemia/reperfusion injury. Because NF-κB is known to play a major role in the pathophysiology of brain ischemia, the present study was undertaken to elucidate whether pioglitazone attenuates ischemic neuronal damage through PPARγ-mediated suppression of NF-κB apoptotic signaling pathway. Permanent middle cerebral artery occlusion (pMCAO) model was induced by using an intraluminal filament technique in rats. Piog was administrated i.p. twice (24 h before and at the time of ischemia insult) or once (10 min after ischemia). The neuroprotection of Piog was analyzed by assessing neurological deficits, infarction volume and morphological changes. The inhibition of NF-κB signaling pathway by Piog was evaluated by detecting the nuclear translocation of NF-κB p65 with immunohistochemistry and its target gene p53 by real-time PCR, and the expression of phospholated NF-κB p65 (p- NF-κB p65) in primary cultured neurons and the protein levels of IκBα and p-ERK in the ischemic cortex or striatum with Western blotting analysis. The contribution of a PPARγ mechanism to Piog's inhibitory effects on NF-κB and neuroprotection was evaluated by pretreatment with the PPARγ irreversible antagonist GW9662. In vitro ischemia in cultured primary neurons was induced by the oxygen-glucose deprivation (OGD) and the protective effect of Piog on cultured neurons was measured by lactate dehydrogenase (LDH) assay. Piog (0.5, 1, 2 mg/kg) reduced infarction volume, and improved morphological changes and motor deficits. Piog markedly up-regulated the protein levels of IκBα or p-ERK 6 h or 12 h after ischemia. Piog reduced the nuclear translocation of NF-κB p65 in the ischemic cortical cells and repressed the expression of p53 12 h after ischemia. Pre-treatment with GW9662 blocked Piog-elicited reduction in infarction volume, the increase in protein levels of IκBα and p-ERK, the reduction in the nuclear translocation of NF-κB subunit p65 and the repression of p53 mRNA expression. In addition, Piog attenuated the OGD-induced neuronal damage and inhibited the OGD-induced increases in p- NF-κB p65 in neurons. The present findings suggest that Piog's neuroprotection appears to be associated with PPARγ-mediated suppression of NF-κB signaling pathway.
Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, is known to have important roles in proliferation and growth of tumor cells and in chemotherapy resistance. Yet, the ...mechanisms underlying how NAC1 contributes to drug resistance remain largely unclear. We report here that autophagy was involved in NAC1-mediated resistance to cisplatin, a commonly used chemotherapeutic drug in the treatment of ovarian cancer. We found that treatment with cisplatin caused an activation of autophagy in ovarian cancer cell lines, A2780, OVCAR3 and SKOV3. We further demonstrated that knockdown of NAC1 by RNA interference or inactivation of NAC1 by inducing the expression of a NAC1 deletion mutant that contains only the BTB/POZ domain significantly inhibited the cisplatin-induced autophagy, resulting in increased cisplatin cytotoxicity. Moreover, inhibition of autophagy and sensitization to cisplatin by NAC1 knockdown or inactivation were accompanied by induction of apoptosis. To confirm that the sensitizing effect of NAC1 inhibition on the cytotoxicity of cisplatin was attributed to suppression of autophagy, we assessed the effects of the autophagy inhibitors 3-methyladenosine and chloroquine, and small interfering RNAs (siRNAs) targeting beclin 1 or Atg5 on the cytotoxicity of cisplatin. Treatment with 3-methyladenosine, chloroquine or beclin 1 and Atg5-targeted siRNA also enhanced the sensitivity of SKOV3, A2780 and OVCAR3 cells to cisplatin, indicating that suppression of autophagy indeed renders tumor cells more sensitive to cisplatin. Regulation of autophagy by NAC1 was mediated by the high-mobility group box 1 (HMGB1), as the functional status of NAC1 was associated with the expression, translocation and release of HMGB1. The results of our study not only revealed a new mechanism determining cisplatin sensitivity but also identified NAC1 as a novel regulator of autophagy. Thus, the NAC1-mediated autophagy may be exploited as a new target for enhancing the efficacy of cisplatin against ovarian cancer and other types of malignancies.
We demonstrate a quantum walk with time-dependent coin bias. With this technique we realize an experimental single-photon one-dimensional quantum walk with a linearly ramped time-dependent coin flip ...operation and thereby demonstrate two periodic revivals of the walker distribution. In our beam-displacer interferometer, the walk corresponds to movement between discretely separated transverse modes of the field serving as lattice sites, and the time-dependent coin flip is effected by implementing a different angle between the optical axis of half-wave plate and the light propagation at each step. Each of the quantum-walk steps required to realize a revival comprises two sequential orthogonal coin-flip operators, with one coin having constant bias and the other coin having a time-dependent ramped coin bias, followed by a conditional translation of the walker.
Summary
Hepatitis B virus surface antigen (HBsAg) plays an important role in maintaining the tolerance and may interfere with host innate and adaptive immune responses; therefore, novel therapeutic ...strategies to reduce HBsAg loads in patients infected with hepatitis B virus (HBV) are emerging as an attractive but challenging issue. Metformin could regulate hepatic metabolism while the latter interacts with HBV infection. We hypothesized that metformin could affect HBsAg expression and HBV replication and may work synergistically when combined with current antivirals. In our study, a notably inhibitory effect on HBsAg production, as well as a moderate inhibition in HBV replication and HBeAg expression was observed following metformin treatment. The 50% effective concentration (EC50) for extracellular HBsAg and intracellular HBsAg in HBV‐producing HepG2.2.15 cells was 2.85 mm and 2.75 mm, respectively, with a similarly selective index of about 18. When administered in combination, metformin enhanced the inhibitory effects of interferon‐α2b on HBsAg expression and HBV replication and provided a complimentary role in HBsAg expression for lamivudine (LMV). This novel action of metformin derives partially from its inhibition on multiple HBV cis‐acting elements. By the virtues of preferably hepatocyte distribution and safety profile, collectively, our results suggest that metformin would be potentially clinically helpful as an HBsAg production inhibitor.
Objectives
Epidermal growth factor receptor (EGFR) gene amplification and the EGFRvIII mutation may have prognostic value in patients with glioblastoma. This meta‐analysis was to determine whether ...EGFR gene amplification or the EGFRvIII mutation are predictors of survival in patients with glioblastoma and anaplastic astrocytoma.
Materials and methods
Medline, the Cochrane Central Register of Controlled Trials, EMBASE, and Google Scholar databases were searched until July 31, 2014. Studies were selected for inclusion in the analysis if they included patients with anaplastic astrocytoma and/or glioblastoma, EGFR and/or EGFRvIII mutation status was reported, and overall survival (OS) data were reported.
Results
Of 113 articles initially identified, only eight contained data with respect to the outcome of interest and were included in the meta‐analysis. The number of cases ranged from 14 to 268, and the majority of patients were 60 or more years of age. There was no significant difference in OS between EGFR amplification‐positive and EGFR amplification‐negative glioblastoma patients (pooled hazard ratio HR = 1.101, 95% confidence interval CI 0.845, 1.434, P = 0.475) or anaplastic astrocytoma patients (pooled HR = 1.455, 95% CI 0.852, 2.482, P = 0.169). There was no significant difference in OS between EGFRvIII‐positive and EGFRvIII‐negative glioblastoma patients (pooled HR = 1.321, 95% CI: 0.881–1.981, P = 0.178). Significant heterogeneity existed between the studies, and the significance changed when the analysis was performed with studies removed in turn.
Conclusions
There is insufficient evidence that either EGFR amplification or the EGFRvIII mutation has prognostic value in patients with glioblastoma.
The interaction between dynamic recrystallization (DRX) and texture evolution of AZ80 magnesium alloy during hot deformation was investigated by EBSD analysis. A series of compression experiments ...along extrusion (ED) and radius (RD) direction were carried out on the as-extruded AZ80 magnesium alloy with <101‾0>//ED fiber texture at 200–300 °C. The results show that there are a more homogeneous microstructure and a stronger softening trend on the true stress-strain curves in ED than in RD. Texture in ED tends to rotate towards the //ED basal texture and its total intensity weakens, while the <101‾0>//ED and <112‾0>//ED fiber texture in RD present a sharpening phenomenon. The compression in ED activates discontinuous dynamic recrystallization (DDRX) mechanism and forms dynamically recrystallized grains with random orientation, which is beneficial to optimize the texture and improve the formability of AZ80 magnesium alloy. The deformation in RD activates the continuous dynamic recrystallization (CDRX) mechanism and produces dynamically recrystallized grains following the orientation of parent grains, which results in the sharpening of the initial texture and is unfavorable for weakening the anisotropy of AZ80 magnesium alloy.
beta decay of proton-rich nuclei plays an important role in exploring isospin mixing. The beta decay of P-26 at the proton drip line is studied using double-sided silicon strip detectors operating in ...conjunction with high-purity germanium detectors. The T = 2 isobaric analog state (IAS) at 13 055 keV and two new high-lying states at 13 380 and 11 912 keV in Si-26 are unambiguously identified through beta-delayed two-proton emission (beta 2p). Angular correlations of two protons emitted from Si-26 excited states populated by P-26 beta decay are measured, which suggests that the two protons are emitted mainly sequentially. We report the first observation of a strongly isospin-mixed doublet that deexcites mainly via two-proton decay. The isospin mixing matrix element between the Si-26 IAS and the nearby 13 380-keV state is determined to be 130(21) keV, and this result represents the strongest mixing, highest excitation energy, and largest level spacing of a doublet ever observed in beta-decay experiments.
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