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Molecular Design of Chemical Compounds with Prescribed Properties from QSAR Models Containing the Hosoya Index
Get PDFImpaired Dual-Specificity Protein Phosphatase DUSP4 Reduces Corticosteroid Sensitivity s
Get PDFABSTRACT We have reported that phosphorylation of the glucocorticoid receptor (GR) at Ser 226 reduces GR nuclear translocation, resulting in corticosteroid insensitivity in patients with severe asthmas. A serine/threonine protein phosphatase 2A, which regulates c-Jun N-terminal kinase (JNK) 1 and GR-Ser 226 signaling, is involved in this mechanism. Here, we further explored protein kinase dualspecificity phosphatases (DUSPs) with the ability to dephosphorylate JNK, and identified DUSP4 as a phosphatase involved in the regulation of corticosteroid sensitivity. The effects of knocking down DUSPs (DUSP1, 4, 8, 16, and 22) by small interfering RNA (siRNA) were evaluated in a monocytic cell line (U937). Corticosteroid sensitivity was determined by dexamethasone enhancement of FK506-binding protein 51 or inhibition of tumor necrosis factor a (TNFa)-induced interferon g and interleukin 8 expression and GR translocation from cell cytoplasm to nucleus. The nuclear/ cytoplasmic GR, phosphorylation levels of GR-Ser 226 and JNK1, coimmunoprecipitated GR-JNK1-DUSP4, and DUSP4 expression were analyzed by western blotting and/or imaging flow cytometry. Phosphatase activity of immunoprecipitated (IP)-DUSP4 was measured by fluorescence-based assay. Knockdown of DUSP4 enhanced phosphorylation of GR-Ser 226 and JNK1 and reduced GR nuclear translocation and corticosteroid sensitivity. Coimmunoprecipitation experiments showed that DUSP4 is associated with GR and JNK1. In peripheral blood mononuclear cells from severe asthmatics, DUSP4 expression was reduced versus healthy subjects and negatively correlated with phosphorylation levels of GR-Ser 226 and JNK1. Formoterol enhanced DUSP4 activity and restored corticosteroid sensitivity reduced by DUSP4 siRNA. In conclusion, DUSP4 regulates corticosteroid sensitivity via dephosphorylation of JNK1 and GR-Ser 226 . DUSP4 activation by formoterol restores impaired corticosteroid sensitivity, indicating that DUSP4 is crucial in regulating corticosteroid sensitivity, and therefore might be a novel therapeutic target in severe asthma
Effects of Acupuncture Applied to Sanyinjiao with Different Stimuli on Uterine Contraction and Microcirculation in Rats with Dysmenorrhea of Cold Coagulation Syndrome
No full textIn this study, we try to evaluate the effects of acupuncture stimulation with different amounts at Sanyinjiao (SP6) on uterine contraction and uterus microcirculation in rats with dysmenorrhea of cold coagulation syndrome and to explore whether there is direct relativity between "De qi" and needle stimulus intensity. Diestrus female rats were randomly divided into 4 groups, including saline control group, model control group, "A" stimulus group (with strong stimulus), and "B" stimulus group (with weak stimulus). We found that dysmenorrhea rats of the cold coagulation syndrome present a high intensity in uterine tension and high contraction of microvascular diameter. Acupuncture applied with two different stimuli could relieve the symptoms, but, compared with "B" stimulus, "A" stimulus leads to better outcomes on reducing uterine contraction and increasing diameter of uterine microvascular; moreover, hand manipulation during needling mediates the curative effect on the microvascular diameter. Our finding indicates that using thick needles and deep insertion with hand manipulation are more effective and achieve desired level of "De qi" in dysmenorrhea rats
Interest rates and infl ation: What are the links?
No full textinfl ation. It is also argued that the route through the exchange rate does not support the view that higher interest rates will dampen down infl ation (though it may lower prices relative to what they would have been). It is further argued that the link from the level of economic activity to the rate of infl ation is theoretically dubious. In the last section it is briefl y indicated that there is a lack of empirical support for any strong link from interest rate to infl ation. JEL classifi cations: E31, E40, E43, E5
R.R.: Agents and Workflow – An Intimate Connection or Just Friends?. Panel report
No full textAbstrac
Normalization Propagation: A Parametric Technique for Removing Internal Covariate Shift in Deep Networks Venu Govindaraju
No full textAbstract While the authors of Batch Normalization (BN) identify and address an important problem involved in training deep networks-Internal Covariate Shift-the current solution has certain drawbacks. For instance, BN depends on batch statistics for layerwise input normalization during training which makes the estimates of mean and standard deviation of input (distribution) to hidden layers inaccurate due to shifting parameter values (especially during initial training epochs). Another fundamental problem with BN is that it cannot be used with batch-size 1 during training. We address these drawbacks of BN by proposing a non-adaptive normalization technique for removing covariate shift, that we call Normalization Propagation. Our approach does not depend on batch statistics, but rather uses a data-independent parametric estimate of mean and standard-deviation in every layer thus being computationally faster compared with BN. We exploit the observation that the pre-activation before Rectified Linear Units follow Gaussian distribution in deep networks, and that once the first and second order statistics of any given dataset are normalized, we can forward propagate this normalization without the need for recalculating the approximate statistics for hidden layers
Felodipine-Metoprolol Combination Tablet: Maintained Health-Related Quality of Life in the Presence of Substantial Blood Pressure Reduction
No full textThe Effect of Latitude on Carbon, Nitrogen and Oxygen Stable Isotope Ratios in Foliage and in Nitric-oxide ions of Aerosols
No full textABSTRACT: Cosmic rays in the upper troposphere (9000 meters to 15000 meters) initiate the following nuclear chemical reaction: 1n + 14N => 14C + 1H. Previous research has shown a strong effect of latitude on the abundance of neutrons from cosmic rays. However, to date, there has been little exploration of the relationship between the latitude effect for cosmic-ray neutrons and latitudinal variations of stable isotope ratios in aerosols and foliage. In this study, aerosol samples (PM 4.5) and foliage samples were collected in Singapore in November 2009, February and July 2010 and in Fairbanks, Alaska, U.S.A. in January, April and September 2010. The average value of delta 15/14N in foliage in Fairbanks was -1.84 [per mil], whereas the average value in Singapore was -1.3 [per mil]. These results show a clear latitude effect on delta 15/14N in foliage. Furthermore, the average value of delta 15/14N in the nitric-oxide substances in the aerosol samples in Fairbanks was -2.70 [per mil], whereas the average value in Singapore was +7.61 [per mil], demonstrating that delta 15/14N in nitric-oxide substances from aerosol samples also experiences a latitude effect. In both Singapore and Fairbanks, it was observed that values of delta 15/14N in nitric-oxide substances from aerosols were correlated with declination. The value of delta 15/14N in nitric-oxide substances from aerosols in Fairbanks increased with increasing declination due to more active conversions from 14 N to 14 C by neutron bombardment
Analytical solution for estimation of temperature-dependent material properties of metals using modified morse potential
No full textSummary An atomic-level analytical solution, together with a modified Morse potential, has been developed to estimate temperature-dependent thermal expansion coefficients (CTE) and elastic characteristics of bulk metals. In this study, inter-atomic forces are considered as a set of anharmonic oscillator networks which can be described by Morse potential, while the material properties can be defined by these inter-atomic forces; when temperature increases, the vibration of the anharmonic oscillator causes the phenomenon of temperature-dependent material properties. The results of analysis showed that the original Morse potential can give a reasonable prediction of the thermal expansion coefficients and elastic constants of metals at room temperature; however, it has difficulties in giving an accurate result at low and high temperatures. Therefore, to overcome the deficiency, a temperaturedependent modified Morse potential is developed and validated with various metals
Pilot Of Spontaneous Breathing Vs. Ventilated Model For Hemorrhage And Resuscitation In The Rabbit
No full textAbstract Introduction: Most models of hemorrhage and resuscitation do not use an anesthetic with spontaneous ventilation on room air; this may be a better human trauma simulatio