We report the first results of the LISA Pathfinder in-flight experiment. The results demonstrate that two free-falling reference test masses, such as those needed for a space-based gravitational wave ...observatory like LISA, can be put in free fall with a relative acceleration noise with a square root of the power spectral density of 5.2 +/- 0.1 fm s(exp -2)/square root of Hz, or (0.54 +/- 0.01) x 10(exp -15) g/square root of Hz, with g the standard gravity, for frequencies between 0.7 and 20 mHz. This value is lower than the LISA Pathfinder requirement by more than a factor 5 and within a factor 1.25 of the requirement for the LISA mission, and is compatible with Brownian noise from viscous damping due to the residual gas surrounding the test masses. Above 60 mHz the acceleration noise is dominated by interferometer displacement readout noise at a level of (34.8 +/- 0.3) fm square root of Hz, about 2 orders of magnitude better than requirements. At f less than or equal to 0.5 mHz we observe a low-frequency tail that stays below 12 fm s(exp -2)/square root of Hz down to 0.1 mHz. This performance would allow for a space-based gravitational wave observatory with a sensitivity close to what was originally foreseen for LISA.
Correlating electromechanical and dielectric properties with nanometre-scale order is the defining challenge for the development of piezoelectric oxides. Current lead (Pb)-based relaxor ...ferroelectrics can serve as model systems with which to unravel these correlations, but the nature of the local order and its relation to material properties remains controversial. Here we employ recent advances in diffuse scattering instrumentation to investigate crystals that span the phase diagram of PbMg
Nb
O
-xPbTiO
(PMN-xPT) and identify four forms of local order. From the compositional dependence, we resolve the coupling of each form to the dielectric and electromechanical properties observed. We show that relaxor behaviour does not correlate simply with ferroic diffuse scattering; instead, it results from a competition between local antiferroelectric correlations, seeded by chemical short-range order, and local ferroic order. The ferroic diffuse scattering is strongest where piezoelectricity is maximal and displays previously unrecognized modulations caused by anion displacements. Our observations provide new guidelines for evaluating displacive models and hence the piezoelectric properties of environmentally friendly next-generation materials.
Previously, we reported that Akt inactivation determines the sensitivity of hepatocellular carcinoma (HCC) cells to bortezomib. In this study, we report that cancerous inhibitor of protein ...phosphatase 2A (CIP2A), a cellular inhibitor of protein phosphatase 2A (PP2A), mediates the apoptotic effect of bortezomib in HCC. Silencing PP2A by small interference RNA (siRNA) abolishes bortezomib-induced down-regulation of phospho-Akt and apoptosis. Bortezomib increases PP2A activity in sensitive HCC cells, including Sk-Hep1, Hep3B and Huh-7, but not in resistant PLC5 cells. Bortezomib down-regulates CIP2A in a dose- and time-dependent manner in all sensitive HCC cells, whereas no alterations in CIP2A were found in resistant PLC5 cells. Knockdown of CIP2A by siRNA restored bortezomib's effects on apoptosis and PP2A activity in PLC5 cells. Moreover, over-expression of CIP2A up-regulated phospho-Akt and protected Sk-Hep1 cells from bortezomib-induced apoptosis. It is significant that, ectopic expression of CIP2A decreased Akt-related PP2A activity, whereas silencing CIP2A increased this activity, indicating that CIP2A negatively regulates Akt-related PP2A activity in HCC cells, furthermore, our in vivo data showed that bortezomib down-regulates CIP2A and up-regulates PP2A activity in Huh-7 tumors, but not in PLC5 tumors. In conclusion, inhibition of CIP2A determines the effects of bortezomib on apoptosis and PP2A-dependent Akt inactivation in HCC.
The metabolic syndrome may cause disease progression in patients with chronic hepatitis B (CHB). However, the interactions between hepatitis B virus (HBV) infection and metabolic factors remain ...unknown. We investigated the association of HBV infection with metabolic profiles in HBV‐infected and noninfected subjects. In addition, the impacts of serum HBV DNA level on metabolic profiles were studied. Initially, a case–control analysis of patients with and without chronic HBV infection was performed. The HBV group consisted of 322 patients with chronic HBV infection, and the control group consisted of 870 matched subjects without HBV infection. Fasting blood glucose, lipid profiles and adiponectin levels were compared. The results were then confirmed in a second retrospective cohort study in 122 CHB patients with serum HBV DNA levels and HOMA‐IR index values. In the case–control analysis, the HBV group had significantly higher serum adiponectin, but lower triglyceride (TG) and high‐density lipoprotein cholesterol (HDL) levels than the control group. These relationships already existed in subjects younger than 45 years of age and were modified by serum alanine aminotransferase (ALT) levels. In the retrospective cohort, serum HBV DNA levels were negatively proportional to TG levels, but not to other metabolic parameters. Moreover, this relationship was significant only in subjects with higher ALT levels. Compared with healthy adults, patients with chronic HBV infection have significantly higher serum adiponectin, but lower TG and HDL levels. These relationships are modified by ALT levels and already exist in middle‐age patients with chronic HBV infection, implying HBV may interact with host metabolism.
The authors have decomposed the anthropogenic aerosol radiative forcing into direct contributions from each aerosol species to the planetary energy balance through absorption and scattering of solar ...radiation, indirect effects of anthropogenic aerosol on solar and infrared radiation through droplet and crystal nucleation on aerosol, and semidirect effects through the influence of solar absorption on the distribution of clouds. A three-mode representation of the aerosol in version 5.1 of the Community Atmosphere Model (CAM5.1) yields global annual mean radiative forcing estimates for each of these forcing mechanisms that are within 0.1 W m−2of estimates using a more complex seven-mode representation that distinguishes between fresh and aged black carbon and primary organic matter. Simulating fresh black carbon particles separately from internally mixed accumulation mode particles is found to be important only near fossil fuel sources. In addition to the usual large indirect effect on solar radiation, this study finds an unexpectedly large positive longwave indirect effect (because of enhanced cirrus produced by homogenous nucleation of ice crystals on anthropogenic sulfate), small shortwave and longwave semidirect effects, and a small direct effect (because of cancelation and interactions of direct effects of black carbon and sulfate). Differences between the three-mode and seven-mode versions are significantly larger (up to 0.2 W m−2) when the hygroscopicity of primary organic matter is decreased from 0.1 to 0 and transfer of the primary carbonaceous aerosol to the accumulation mode in the seven-mode version requires more hygroscopic material coating the primary particles. Radiative forcing by cloudborne anthropogenic black carbon is only −0.07 W m−2.
ABSTRACT
The European Pulsar Timing Array (EPTA) collaboration has recently released an extended data set for six pulsars (DR2) and reported evidence for a common red noise signal. Here we present a ...noise analysis for each of the six pulsars. We consider several types of noise: (i) radio frequency independent, ‘achromatic’, and time-correlated red noise; (ii) variations of dispersion measure and scattering; (iii) system and band noise; and (iv) deterministic signals (other than gravitational waves) that could be present in the PTA data. We perform Bayesian model selection to find the optimal combination of noise components for each pulsar. Using these custom models we revisit the presence of the common uncorrelated red noise signal previously reported in the EPTA DR2 and show that the data still supports it with a high statistical significance. Next, we confirm that there is no preference for or against the Hellings–Downs spatial correlations expected for the stochastic gravitational-wave background. The main conclusion of the EPTA DR2 paper remains unchanged despite a very significant change in the noise model of each pulsar. However, modelling the noise is essential for the robust detection of gravitational waves and its impact could be significant when analysing the next EPTA data release, which will include a larger number of pulsars and more precise measurements.
Glioblastoma multiforme (GBM) cells are resistant to anticancer drugs. Cancer stem cells (CSCs) are a key mediator of chemoresistance. We have reported that disulfiram (DS), an aldehyde dehydrogenase ...(ALDH) inhibitor, targets breast CSC-like cells. In this study, the effect of DS and combination of DS and gemcitabine (dFdC) on GBM cells and GBM stem-like cells was investigated.
1-(4,5-Dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), combination index (CI)-isobologram, western blot, luciferase reporter gene assay, electrophoretic mobility-shift assay and ALDH analysis were used in this study.
Disulfiram is cytotoxic in GBM cell lines in a copper (Cu)-dependent manner. Disulfiram/copper enhances the cytotoxicity of dFdC. Combination index-isobologram analysis indicates a synergistic effect between DS/Cu and dFdC. Disulfiram/copper induces reactive oxygen species (ROS), activates JNK and p38 pathways and inhibits nuclear factor-kappa B activity in GBM cell lines. Disulfiram/copper may trigger intrinsic apoptotic pathway via modulation of the Bcl2 family. Disulfiram/copper abolishes stem-like cell population in GBM cell lines.
Our findings indicate that the cytotoxicity of DS/Cu and the enhancing effect of DS/Cu on the cytotoxicity of dFdC in GBM stem-like cells may be caused by induction of ROS and inhibition of both ALDH and the NFkB pathway. Both DS and dFdC can traverse the blood-brain barrier. Further study may lead them into GBM chemotherapy.
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death, reflecting the need for better understanding the oncogenesis, and developing new diagnostic and therapeutic targets for the ...malignancy. Emerging evidence suggests that small nucleolar RNAs (snoRNAs) have malfunctioning roles in tumorigenesis. Our recent study demonstrated that small nucleolar RNA 42 (SNORA42) was overexpressed in lung tumors. Here, we investigate the role of SNORA42 in tumorigenesis of NSCLC. We simultaneously assess genomic dosages and expression levels of SNORA42 and its host gene, KIAA0907, in 10 NSCLC cell lines and a human bronchial epithelial cell line. We then determine in vitro functional significance of SNORA42 in lung cancer cell lines through gain- and loss-of-function analyses. We also inoculate cancer cells with SNORA42-siRNA into mice through either tail vein or subcutaneous injection. We finally evaluate expression level of SNORA42 on frozen surgically resected lung tumor tissues of 64 patients with stage I NSCLC by using quantitative reverse transcriptase PCR assay. Genomic amplification and associated high expression of SNORA42 rather than KIAA0907 are frequently observed in lung cancer cells, suggesting that SNORA42 overexpression is activated by its genomic amplification. SNORA42 knockdown in NSCLC cells inhibits in vitro and in vivo tumorigenicity, whereas enforced SNORA42 expression in bronchial epitheliums increases cell growth and colony formation. Such pleiotropy of SNORA42 suppression could be achieved at least partially through increased apoptosis of NSCLC cells in a p53-dependent manner. SNORA42 expression in lung tumor tissue specimens is inversely correlated with survival of NSCLC patients. Therefore, SNORA42 activation could have an oncogenic role in lung tumorigenesis and provide potential diagnostic and therapeutic targets for the malignancy.
Calponin is an actin filament-associated regulatory protein expressed in smooth muscle and many types of non-muscle cells. Three homologous genes, CNN1, CNN2 and CNN3, encoding calponin isoforms 1, ...2, and 3, respectively, are present in vertebrate species. All three calponin isoforms are actin-binding proteins with functions in inhibiting actin-activated myosin ATPase and stabilizing the actin cytoskeleton, while each isoform executes different physiological roles based on their cell type-specific expressions. Calponin 1 is specifically expressed in smooth muscle cells and plays a role in fine-tuning smooth muscle contractility. Calponin 2 is expressed in both smooth muscle and non-muscle cells and regulates multiple actin cytoskeleton-based functions. Calponin 3 participates in actin cytoskeleton-based activities in embryonic development and myogenesis. Phosphorylation has been extensively studied for the regulation of calponin functions. Cytoskeleton tension regulates the transcription of CNN2 gene and the degradation of calponin 2 protein. This review summarizes our knowledge learned from studies over the past three decades, focusing on the evolutionary lineage of calponin isoform genes, their tissue- and cell type-specific expressions, structure–function relationships, and mechanoregulation.
In the months since the publication of the first results, the noise performance of LISA Pathfinder has improved because of reduced Brownian noise due to the continued decrease in pressure around the ...test masses, from a better correction of noninertial effects, and from a better calibration of the electrostatic force actuation. In addition, the availability of numerous long noise measurement runs, during which no perturbation is purposely applied to the test masses, has allowed the measurement of noise with good statistics down to 20 μHz. The Letter presents the measured differential acceleration noise figure, which is at (1.74±0.05) fm s^{-2}/sqrtHz above 2 mHz and (6±1)×10 fm s^{-2}/sqrtHz at 20 μHz, and discusses the physical sources for the measured noise. This performance provides an experimental benchmark demonstrating the ability to realize the low-frequency science potential of the LISA mission, recently selected by the European Space Agency.
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