Possible origin of β\beta-relaxation in amorphous metal alloys from atomic-mass differences of the constituents

We employ an atomic-scale theory within the framework of nonaffine lattice dynamics to uncover the origin of the Johari-Goldstein (JG) $\beta$-relaxation in metallic glasses (MGs). Combining simulation and experimental data with our theoretical approach, we reveal that the large mass asymmetry between the elements in a La$_{60}$Ni$_{15}$Al$_{25}$ MG leads to a clear separation in the respective relaxation time scales, giving strong evidence that JG relaxation is controlled by the lightest atomic species present. Moreover, we show that only qualitative features of the vibrational density of states determine the overall observed mechanical response of the glass, paving the way for a possible unified theory of secondary relaxations in glasses

Identification and Characterization of \u3cem\u3eOGG1\u3c/em\u3e Mutations in Patients with Alzheimer\u27s Disease

Patients with Alzheimer\u27s disease (AD) exhibit higher levels of 8-oxo-guanine (8-oxoG) DNA lesions in their brain, suggesting a reduced or defective 8-oxoG repair. To test this hypothesis, this study investigated 14 AD patients and 10 age-matched controls for mutations of the major 8-oxoG removal gene OGG1. Whereas no alterations were detected in any control samples, four AD patients exhibited mutations in OGG1, two carried a common single base (C796) deletion that alters the carboxyl terminal sequence of OGG1, and the other two had nucleotide alterations leading to single amino acid substitutions. In vitro biochemical assays revealed that the protein encoded by the C796-deleted OGG1 completely lost its 8-oxoG glycosylase activity, and that the two single residue-substituted OGG1 proteins showed a significant reduction in the glycosylase activity. These results were consistent with the fact that nuclear extracts derived from a limited number of AD patients with OGG1 mutations exhibited greatly reduced 8-oxoG glycosylase activity compared with age-matched controls and AD patients without OGG1 alterations. Our findings suggest that defects in OGG1 may be important in the pathogenesis of AD in a significant fraction of AD patients and provide new insight into the molecular basis for the disease

Tumor Suppressor Spred2 Interaction with LC3 Promotes Autophagosome Maturation and Induces Autophagy-Dependent Cell Death

The tumor suppressor Spred2 (Sprouty-related EVH1 domain-2) induces cell death in a variety of cancers. However, the underlying mechanism remains to be elucidated. Here we show that Spred2 induces caspase-independent but autophagy-dependent cell death in human cervical carcinoma HeLa and lung cancer A549 cells. We demonstrate that ectopic Spred2 increased both the conversion of microtubule-associated protein 1 light chain 3 (LC3), GFP-LC3 puncta formation and p62/SQSTM1 degradation in A549 and HeLa cells. Conversely, knockdown of Spred2 in tumor cells inhibited upregulation of autophagosome maturation induced by the autophagy inducer Rapamycin, which could be reversed by the rescue Spred2. These data suggest that Spred2 promotes autophagy in tumor cells. Mechanistically, Spred2 co-localized and interacted with LC3 via the LC3-interacting region (LIR) motifs in its SPR domain. Mutations in the LIR motifs or deletion of the SPR domain impaired Spred2-mediated autophagosome maturation and tumor cell death, indicating that functional LIR is required for Spred2 to trigger tumor cell death. Additionally, Spred2 interacted and co-localized with p62/SQSTM1 through its SPR domain. Furthermore, the co-localization of Spred2, p62 and LAMP2 in HeLa cells indicates that p62 may be involved in Spred2-mediated autophagosome maturation. Inhibition of autophagy using the lysosomal inhibitor chloroquine, reduced Spred2-mediated HeLa cell death. Silencing the expression of autophagy-related genes ATG5, LC3 or p62 in HeLa and A549 cells gave similar results, suggesting that autophagy is required for Spred2-induced tumor cell death. Collectively, these data indicate that Spred2 induces tumor cell death in an autophagy-dependent manner

Efficacy and Safety of Prophylactic Vaccines against Cervical HPV Infection and Diseases among Women: A Systematic Review & Meta-Analysis

<p>Abstract</p> <p>Background</p> <p>We conducted a systematic review and meta-analysis to assess efficacy and safety of prophylactic HPV vaccines against cervical cancer precursor events in women.</p> <p>Methods</p> <p>Randomized-controlled trials of HPV vaccines were identified from MEDLINE, Cochrane Central Register of Controlled Trials, conference abstracts and references of identified studies, and assessed by two independent reviewers. Efficacy data were synthesized using fixed-effect models, and evaluated for heterogeneity using I²statistic.</p> <p>Results</p> <p>Seven unique trials enrolling 44,142 females were included. The fixed-effect Relative Risk (RR) and 95% confidence intervals were 0.04 (0.01-0.11) and 0.10 (0.03-0.38) for HPV-16 and HPV 18-related CIN2+ in the per-protocol populations (PPP). The corresponding RR was 0.47 (0.36-0.61) and 0.16 (0.08-0.34) in the intention-to-treat populations (ITT). Efficacy against CIN1+ was similar in scale in favor of vaccine. Overall vaccines were highly efficacious against 6-month persistent infection with HPV 16 and 18, both in the PPP cohort (RR: 0.06 [0.04-0.09] and 0.05 [0.03-0.09], respectively), and the ITT cohorts (RR: 0.15 [0.10-0.23] and 0.24 [0.14-0.42], respectively). There was limited prophylactic effect against CIN2+ and 6-month persistent infections associated with non-vaccine oncogenic HPV types. The risk of serious adverse events (RR: 1.00, 0.91-1.09) or vaccine-related serious adverse events (RR: 1.82; 0.79-4.20) did not differ significantly between vaccine and control groups. Data on abnormal pregnancy outcomes were underreported.</p> <p>Conclusions</p> <p>Prophylactic HPV vaccines are safe, well tolerated, and highly efficacious in preventing persistent infections and cervical diseases associated with vaccine-HPV types among young females. However, long-term efficacy and safety needs to be addressed in future trials.</p

Intrathecal Injection of Spironolactone Attenuates Radicular Pain by Inhibition of Spinal Microglia Activation in a Rat Model

Microglia might play an important role in nociceptive processing and hyperalgesia by neuroinflammatory process. Mineralocorticoid receptor (MR) expressed on microglia might play a central role in the modulation of microglia activity. However the roles of microglia and MR in radicular pain were not well understood. This study sought to investigate whether selective MR antagonist spironolactone develop antinociceptive effects on radicular pain by inhibition neuroinflammation induced by spinal microglia activation.Radicular pain was produced by chronic compression of the dorsal root ganglia with SURGIFLO™. The expression of microglia, interleukin beta (IL-1β), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), NR1 subunit of the NMDA receptor (t-NR1), and NR1 subunit phosphorylated at Ser896 (p-NR1) were also markedly up-regulated. Intrathecal injection of spironolactone significantly attenuated pain behaviors as well as the expression of microglia, IL-1β, TNF-α, t-NR1, and p-NR1, whereas the production of IL-6 wasn't affected.These results suggest that intrathecal delivery spironolactone has therapeutic effects on radicular pain in rats. Decreasing the activation of glial cells, the production of proinflammatory cytokines and down-regulating the expression and phosphorylation of NMDA receptors in the spinal dorsal horn and dorsal root ganglia are the main mechanisms contributing to its beneficial effects

Identification of functional lncRNAs through constructing a lncRNA-associated ceRNA network in myocardial infarction

Myocardial infarction (MI) is a type of coronary heart disease, which refers to the ischemic necrosis of the heart muscle. A large number of studies have discussed the mechanism of MI from the perspective of competing endogenous RNA (ceRNA) network. However, the mechanisms underlying the function of lncRNAs in MI have still not been explained in an explicit manner. Therefore, we constructed a scale-free lncRNA-associated ceRNA network to identify some crucial lncRNAs in MI. Results showed that the given disease genes for MI were involved in the network, the degrees of which were significantly larger than the other nodes of the network. For measuring the network centrality, we then constructed a hub subnetwork. The miRNAs and mRNAs in the hub subnetwork have been validated to function in MI-related biological function. In addition, we identified 2 MI-related functional modules from the lncRNA-associated ceRNA network, which suggested that lncRNA exerted function in local network. Enrichment analysis showed that these functional modules corresponded to some similar and different pathways related to cardiovascular disease. More importantly, 3 MI-related crucial lncRNAs, CTD-3092A11.2, RP5-821D11.7 and CTC-523E23.1 were detected as potential biomarkers, which may be involved in MI-related biological progresses. Our study identified 20 functional lncRNAs based on ceRNA network analysis, which may provide novel diagnosis and therapeutic targets for MI from the ceRNA network perspective

Association between GNAS1 T393C Polymorphism and Therapeutic Efficacy of Tyrosine Kinase Inhibitor in Pretreated Advanced Non-small Cell Lung Cancer with Unknown EGFR Mutation Status

Background and objective Epidermal growth factor receptor (EGFR)-activating mutation predicts excellent response to EGFR tyrosine kinase inhibitors (TKIs). However, lung cancer patients are often with unknown EGFR mutation status because there are little tumor specimen to determine. TKIs induce tumor cell apoptosis which associates with several apoptosis-related genes. To explore the association between GNAS1 T393C polymorphism and therapeutic efficacy of TKI in pretreated advanced non-small cell lung cancer (NCSLC) with unknown EGFR mutation status. Methods A total of 116 patients were recruited for the study from Zhejiang Cancer Hospital, all of whom were treated with gefitinib or erlotinib after failure to prior chemotherapy. We detected the genotype of peripheral blood lymphocytes of patients with GNAS1 T393C polymorphism through polymerase chain reaction (PCR). Statistical analysis was performed by SPSS version 18.0. Results The overall response rate was 29.3%. No significant associations were found among GNAS1 T393C polymorphism and the objective response rate. The disease control rate of patients with GNAS1 T393C CC genotype was lower than that of patients with variant genotype (TT or CT) (46.2% vs 73.8%, P=0.039). Univariate analysis identified gender, smoking history, histology and GNAS1 T393C polymorphism as predictive marker of PFS (P=0.04, P<0.001, P<0.001 and P=0.005). Multivariate analysis of factors, including smoking history, performance status score, histology, GNAS1 T393C polymorphism demonstrated that GNAS1 T393C polymorphism was correlated independently with PFS (P=0.007). Conclusion Our data suggest the role of GNAS1 T393C CC genotype as a poor predictive marker both of DCR and PFS in advanced NSCLC patients treated with tyrosine kinase inhibitor

Numerical Study on Pressure Pulsation in a Slanted Axial-Flow Pump Device under Partial Loads

The 30° slanted axial-flow pump device is widely used in agricultural irrigation and urban drainage in plains areas of China. However, during the actual operation process, the 30° slanted axial-flow pump device is prone to vibration, noise, cracks in the blades, and other phenomena that affect the safe and stable operation of the pump device. In order to analyze the flow pressure pulsation characteristics of the 30° slanted axial-flow pump device under different flow conditions, the time–frequency domain analysis method was used to analyze the pressure pulsation of each flow structure of the 30° slanted axial-flow pump device. The results showed that the internal pulsation law of the elbow oblique inlet flow channel is similar. At the 1.2 Qbep condition, the amplitude fluctuation of the pressure pulsation was small, and the main frequency is 4 times the rotating frequency. The monitoring points at the outlet of the elbow oblique inlet flow channel were affected by the impeller rotation, and the pressure pulsation amplitude was larger than that inside the elbow oblique inlet flow channel. The pressure fluctuation of each monitoring point at the inlet surface of the impeller was affected by the number of blades. There were four peaks and four valleys, and the main frequency was 4 times the rotating frequency. The amplitude of pressure fluctuation increased gradually from the hub to the rim. The main frequency of pressure fluctuation at each monitoring point of the impeller outlet surface was 4 times of the rotating frequency, and the low frequency was rich. The amplitude of pressure fluctuation was significantly lower than that of the impeller inlet. With the increase of flow rate, the peak fluctuation of pressure coefficient decreased gradually, and the amplitude of pressure fluctuation tended to be stable. Under 0.8 Qbep and 1.0 Qbep conditions, the large fluctuation of the pressure fluctuation amplitude on the outlet surface of the guide vane was mainly affected by the low-frequency fluctuation. Under the 1.2 Qbep condition, the pressure fluctuation amplitude changed periodically

Epitope Mapping of Metuximab on CD147 Using Phage Display and Molecular Docking

Metuximab is the generic name of Licartin, a new drug for radioimmunotherapy of hepatocellular carcinoma. Although it is known to be a mouse monoclonal antibody against CD147, the complete epitope mediating the binding of metuximab to CD147 remains unknown. We panned the Ph.D.-12 phage display peptide library against metuximab and got six mimotopes. The following bioinformatics analysis based on mimotopes suggested that metuximab recognizes a conformational epitope composed of more than 20 residues. The residues of its epitope may include T28, V30, K36, L38, K57, F74, D77, S78, D79, D80, Q81, G83, S86, N98, Q100, L101, H102, G103, P104, V131, P132, and K191. The homology modeling of metuximab and the docking of CD147 to metuximab were also performed. Based on the top one docking model, the epitope was predicted to contain 28 residues: AGTVFTTV (23–30), I37, D45, E84, V88, EPMGTANIQLH (92–102), VPP (131–133), Q164, and K191. Almost half of the residues predicted on the basis of mimotope analysis also appear in the docking result, indicating that both results are reliable. As the predicted epitopes of metuximab largely overlap with interfaces of CD147-CD147 interactions, a structural mechanism of metuximab is proposed as blocking the formation of CD147 dimer