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Nickel-based superalloys with and without Co by partial replacement of W were prepared using double vacuum melting. A comparison of the oxidation in air and hot corrosion behaviors under molten 75wt.%Na2SO4+ 25wt.%NaCl at 900 °C were systematically investigated. The results showed that partial replacement of W with Co promoted the formation of chromia scale and consequently decreased the oxidation rate. Besides, the addition of Co also retarded the internal oxidation/nitridation of Al and consequently promoted the growth of Al2O3 scale, which further decreased the scaling rate and improved the adhesion of scale. Moreover, the addition of Co also further improved the hot corrosion resistance under molten Na2SO4–NaCl salts.

Only a few studies about polymyxin B (PMB) against multidrug-resistant gram-negative bacteria (MDR GNB) infection were conducted in liver transplantation recipients (LTRs). The purpose of this study was to investigate the efficacy and safety of PMB in the treatment of MDR-GNB in liver transplant recipients and to determine the risk factors affecting clinical cure and 30-day all-cause mortality.Data of LTRs receiving PMB from January 2016 to February 2020 were collected. Clinical cure and 30-day all-cause mortality were the main efficacy outcomes, while the incidence of nephrotoxicity, neurotoxicity, and hyperpigmentation of PMB was the main safety outcome.Data of 42 LTRs were included. Clinical cure with PMB was observed in 27 recipients (64.3%), and the 30-day all-cause mortality rate was 31.0% (13/42). The incidence of acute kidney injury (AKI), neurotoxicity, and hyperpigmentation was 57.1% (16/28), 4.8% (2/42), and 16.7% (7/42), respectively. Logistic regression analysis showed that Acute Physiology and Chronic Health Evaluation (APACHE) II score (OR, 1.203; 95% CI, 1.016-1.423, p = 0.032) was an independent risk factor for 30-day all-cause mortality, whereas renal replacement therapy (OR, 0.128; 95% CI, 0.019-0.860, p = 0.034) was an independent risk factor for clinical cure with PMB.This is the first study to evaluate the application of PMB in LTRs. If there were no better therapeutic options left for LTRs other than PMB, it can be used against MDR GNB infection in LTRs. We should closely observe adverse events or reactions, and adjust the dose based on the balance of efficacy and safety.

Objective To explore the effect of age on Qingkailing Granules disposition by comparing the pharmacokinetics of geniposide and baicalin in juvenile and adult rats. Methods A simple and rapid LC-MS/MS method was developed and validated to simultaneously determine geniposide and baicalin in rat plasma after a simple protein precipitation. The analytes were separated on an Agilent ZORBAX Extend-C18 column. The mobile phase consisted of acetonitrile and water with 0.1% (volume percent) formic acid at a flow rate of 0.6 mL/min. The ionization was conducted using an ESI source in negative ion mode. Multiple reaction monitoring was used for quantification at transitions of m/z 445.0 → m/z 268.9 for baicalin, m/z 433.2 → m/z 225.0 for geniposide, m/z 431.0 → m/z 341.0 for vitexin (IS). Juvenile and adult rats were administrated Qingkailing Granules (3 g/kg) orally. Plasma concentrations of baicalin and geniposide were determined by LC-MS/MS. Results The linear ranges of the analytes were 1–1000 ng/mL for baicalin and 2–2000 ng/mL for geniposide. The method was successfully applied to compare the pharmacokinetics of the analytes between juvenile and adult rats after oral administration of Qingkailing Granules. AUC was bigger in adult rats, while t1/2 was longer in juvenile rats. Conclusion These results suggested that the absorption and elimination of baicalin and geniposide in juvenile rats was lower than that in adult rats. Additional attention should be paid to the pharmacokinetic difference when Qingkailing Granules were used in children.

2-Hydroxy-4H-quinolizin-4-one scaffolds were enzymatically synthesized by integrating three enzymes including phenylacetate-CoA ligase (PcPCL) from an endophytic fungus Penicillium chrysogenum MT-12, malonyl-CoA synthase (AtMatB) from Arabidopsis thaliana, and a type III polyketide synthase (HsPKS3) from Chinese club moss Huperzia serrata. The findings paved the way to produce these kinds of structurally interesting alkaloids by engineered microorganisms.

Aiming to prepare pervaporation membranes with confined mass transfer channels, multi-walled carbon nanotubes (MWCNTs) with and without functionalization were incorporated into polyurethane (PU) polymer matrices. Scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), transmission electron microscopy (TEM), high-resolution TEM (HRTEM), X-ray diffraction (XRD), Fourier-transform infrared (FTIR), and Raman spectroscopy were employed to explore the effect of functionalization on the morphologies of MWCNTs. The changes in the morphologies of the resulting PU hybrid membrane were then characterized by SEM, TEM, and XRD. Swelling-sorption and pervaporation experiments of benzene and cyclohexane were employed to evaluate the separation performances of various hybrid membranes. The results showed that the introduction of many oxygenated functional groups onto the MWCNT surfaces through functionalization not only efficiently inhibited the MWCNT aggregation but also improved the distributions of the MWCNTs in solvents and polymer materials. Due to the 1D tube structures of the MWCNTs with conjugated π bonds, the addition of well-distributed MWCNTs into the hybrid membranes not only increased the benzene sorption abilities of the membranes but also enhanced the benzene diffusion selectivities due to the strong driving force for the molecules in the confined mass transfer channels. A higher content of well-distributed MWCNTs in the membrane yielded a higher separation performance for benzene. Additionally, increasing the operating temperature in the pervaporation experiments accelerated the molecular motion and weakened the affinity between the benzene molecules and the walls of the MWCNTs, increasing the permeation fluxes of the membranes while decreasing the benzene separation factors.

TiN-TiB 2 nanocrystalline coatings have been in-situ synthesized on the 35CrMnSi steel surface by argon arc cladding process under different welding technological parameters. The calculating method was established for the analysis and calculation of the dilution ratio. The microstructures of the nanocrystalline coatings were characterized by means of X-ray diffraction meter(XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM).Results indicated that the phase of coatings were TiN、TiB 2 、TiB、Cr 23 C 6 and γ-Ni. The welding technological parameters of nanocrystalline coatings have certain effects on the dilution ratio of the clad layer. The tribological behavior of both the substrate and the coatings was investigated in detail. An average microhardness of 1420HV 0.5 was obtained with a cladding current of 120A. While the nanocrystalline coatings shows better wear resistance properties than 35CrMnSi steel.

Twelve new polyketides, penicichrysogenins A-L (1-10, 11a, and 11b) along with five known compounds (12a, 12b, and 13-15) were isolated from the solid substrate fermentation cultures of a Huperzia serrata endophytic fungus Penicillium chrysogenum MT-12. The structures of the new compounds were established using extensive spectroscopic (1D and 2D NMR, IR, and HRESIMS) and calculated electronic circular dichroism (ECD) methods. Compounds 11a/11b and 12a/12b were two pairs of enantiomers successfully separated by chiral HPLC resolution. Compounds 4, 5, 8, 9, 11a/11b, and 12a/12b exhibited inhibition of nitric oxide production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells with IC50 values in the range of 17.5-98.4μM.

Eight new chrysogenolides (A–H (1–8)) and seven known (9–15) 3,5-dimethylorsellinic acid derived meroterpenoids were isolated from the solid substrate fermentation cultures of a Huperzia serrata endophytic fungus, Penicillium chrysogenum MT-12. The structures of the new compounds were elucidated by interpretation of spectroscopic and spectrometric data (1D and 2D NMR, IR, and HRESIMS). The absolute configurations of 1–4 were determined by single-crystal X-ray crystallographic analysis, and those of 5–8 were assigned on the basis of experimental and calculated electronic circular dichroism spectra. Compounds 3, 4, 6, 11, and 12 showed inhibition of nitric oxide production in lipopolysaccharide-activated RAW 264.7 macrophage cells with IC50 values in the range of 4.3–78.2 μM (positive control, indomethacin, IC50 = 33.6 ± 1.4 μM).

A curcuminoids, benzalacetone-, and quinolone-producing type III polyketide synthase (HsPKS3) from Huperzia serrata uniquely catalyzes the formation of unnatural 2-substituted quinolones and 1,3-diketones via head-to-head condensation of two completely different substrates. The broad range of substrate tolerance of HsPKS3 facilitates accessing structurally diverse 2-substituted quinolones and 1,3-diketones.

Five new megastigmane glycosides, urenalobasides A–E (1–5), together with 11 known ones (6–16) were isolated from Urena lobata. Their structures were determined by extensive spectroscopic and spectrometric data (1D and 2D NMR, IR, and HRESIMS) and calculated electronic circular dichroism method. Compounds 1 and 2 are two unusual megastigmanes structurally containing a 6/5 fused ring system. Compound 3 exhibits inhibition of nitric oxide production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells with IC50 value of 53.7 ± 1.0 μM (positive control, dexamethasone, IC50 = 16.6 ± 0.8 μM).

The stain ofFusariumsp. used in 4-chlorophenol (4-CP) degradation was isolated in our laboratory. The effects of pH, Cu2+concentration, carbon source on 4-CP degradation rate byFusariumsp. were investigated. The kinetic equation of 4-CP biodegradation was discussed. It was concluded thatFusariumsp. could grow with 4-CP as the sole carbon and energy source. 4-CP concentration of 50mg/L in the Cu2+concentration of 3mg/L could be degraded completely. The capacity of 4-CP degradation was effectively enhanced by the addiction of phenol. Phenol concentration of 200 mg/L in the pH 7 and the Cu2+concentration of 3 mg/L could be degraded completely. Cu2+at high concentration might reduce the biodegradation rate of 4-CP. The kinetic equation of 4-CP biodegradation could well accord with the zero order equation for 4-CP as the sole carbon source with Cu2+coexistence byFusariumsp..

This paper introduces the research on the Excitation Regulator of the Synchronous Generator with dual CPUs, based on Digital Signal Processor (TMS320LF2812). With the multiple functions of monitoring, analysis, controlling and protection, it overcomes the shortage of the domestic excitation device in terms of self-monitoring and self-protection,which effectively improves device reliability. By analyzing the allocation of reactive load of the interconnected Synchronous Motor group, the model of the digital excitation regulator by Simulink of MATLAB is produced. The results of the simulation show that the proposed regulation model are feasible, satisfying various running demands of the Synchronous Motor and Power System.

The embedded technology has widely applied in the remote monitoring system. This paper is mainly for remote monitoring system project design based on embedded Web technology. And on the basis of the overall system design, it has separately carried on the detailed design and analysis to the software and hardware structure.

The instrumentation is a complexity of the whole system composed by many circuit modules. In order to achieve the detection to the entire system, when the overall system design, the designer must design circuits with judge and test methods suitable for a variety of levels in the case of considering to enables various modules carry on the wrong judgment and state test. This will provide the capabilities of intelligent monitoring and detection for the normal operation of the whole system. This paper has briefly introduced the development trends of modern instrumentation, analyzed the classification level of the failure alarm, given the general intelligent failure alarm circuit and self-test circuit, and provided a theoretical basis and practical reference for the studying of intelligent design of the failure alarm in a variety of instrumentation.

A calandria liquid distributor device was designed for horizontal falling film evaporation. The guide plate was introduced in this, which is easy to manufacture and can effectively reduce splash phenomenon. This paper studies the liquid distribution from the relation between distributive unwell-distributed coefficient and liquid flux of distributor tube and distributor hole. The result showed that the distributive unwell-distributed coefficient of in liquid distributor was decreased along with accretion of liquid flux, as apposed to homogeneous perforated. The unwell-distributed hole coefficient of distributor tube No.0 was increased along with accretion of flux, as apposed to distributor tube No.1 and distributor tube No.2.

In this paper, a new porous coating was formed directly on the surface of titanium metal via anodic oxidation. And by the SEM, the morphology of the coating, which is composed of well-ordered perpendicular nanotubes, was characterized. Moreover, taking deionized water as the test fluid, a visualization study of the coating on its pool boiling heat transfer performance was made. The results demonstrated that compared with the smooth surface, the nucleate boiling heat transfer coefficient can increase 3 times while the nucleate boiling super heat was reduced 30%.

The Fe3Al/Al2O3composites were fabricated by hot-pressing process in this research. The Fe3Al intermetallics compounds powders were fabricated by mechanical alloying and heat treatment, then the Fe3Al powders and Al2O3powders were mixed and the Fe3Al/Al2O3composite powders were prepared, so the Fe3Al/Al2O3composites were fabricated by hot-pressing process at 1300°C for 2h under the pressure of 35MPa. The phase composition and microstructure of the Fe3Al intermetallics compounds powders produced by mechanical alloying and heat treatment were investigated. The phase composition, microstructure and mechanical properties of the Fe3Al/Al2O3composites sintered bulks were investigated. The XRD patterns results showed that there existed Fe3Al phase and Al2O3phase in the sintered composites. The Fe3Al/Al2O3composites sintered bulks exhibited the homogenous and compact microstructure, the Fe3Al particles were homogenously distributed in the Al2O3 matrix, the mean particles size of Fe3Al intermetallics compounds was about 3-4μm. The Fe3Al/Al2O3composites exhibited more homogenous and compact microstructure with the increase of Fe3Al content in the Al2O3matrix. The density and relative density of the Fe3Al/Al2O3composites increased gradually with the increase of Fe3Al content. The fracture strength and fracture toughness of the Fe3Al/Al2O3composites increased gradually with the increase of Fe3Al content. The elastic modulus and hardness (HRA) of the Fe3Al/Al2O3composites decreased gradually with the increase of Fe3Al content.

In the process of using the computer, there will often be some failures which causes the computer not working properly or even cause data loss. This article analyses and discusses the maintenance method of computer hardware from the perspective of common faults of computers, hoping to help you to find the computer's fault quickly and accurately, effectively trouble shooting.

beta-Site amyloid precursor protein (APP)-cleaving enzyme (BACE) 1 cleavage of amyloid precursor protein is an essential step in the generation of the potentially neurotoxic and amyloidogenic A beta 42 peptides in Alzheimer's disease. Although previous mouse studies have shown brain A beta lowering after BACE1 inhibition, extension of such studies to nonhuman primates or man was precluded by poor potency, brain penetration, and pharmacokinetics of available inhibitors. In this study, a novel tertiary carbinamine BACE1 inhibitor, tertiary carbinamine (TC)-1, was assessed in a unique cisterna magna ported rhesus monkey model, where the temporal dynamics of A beta in cerebrospinal fluid (CSF) and plasma could be evaluated. TC-1, a potent inhibitor (IC(50) approximately 0.4 nM), has excellent passive membrane permeability, low susceptibility to P-glycoprotein transport, and lowered brain A beta levels in a mouse model. Intravenous infusion of TC-1 led to a significant but transient lowering of CSF and plasma A beta levels in conscious rhesus monkeys because it underwent CYP3A4-mediated metabolism. Oral codosing of TC-1 with ritonavir, a potent CYP3A4 inhibitor, twice daily over 3.5 days in rhesus monkeys led to sustained plasma TC-1 exposure and a significant and sustained reduction in CSF sAPP beta, A beta 40, A beta 42, and plasma A beta 40 levels. CSF A beta 42 lowering showed an EC(50) of approximately 20 nM with respect to the CSF [TC-1] levels, demonstrating excellent concordance with its potency in a cell-based assay. These results demonstrate the first in vivo proof of concept of CSF A beta lowering after oral administration of a BACE1 inhibitor in a nonhuman primate.

beta-Secretase (BACE) cleavage of amyloid precursor protein (APP) is one of the first steps in the production of amyloid beta peptide Abeta42, the putative neurotoxic species in Alzheimer's disease. Recent studies have shown that BACE1 knockdown leads to hypomyelination, putatively caused by a decline in neuregulin (NRG)-1 processing. In this study, we have tested a potent cell-permeable BACE1 inhibitor (IC(50) approximately 30 nM) by administering it directly into the lateral ventricles of mice, expressing human wild-type (WT)-APP, to determine the consequences of BACE1 inhibition on brain APP and NRG-1 processing. BACE1 inhibition, in vivo, led to a significant dose- and time-dependent lowering of brain Abeta40 and Abeta42. BACE1 inhibition also led to a robust brain secreted (s)APPbeta lowering that was accompanied by an increase in brain sAPPalpha levels. Although an increase in full-length NRG-1 levels was evident in 15-day-old BACE1 homozygous knockout (KO) (-/-) mice, in agreement with previous studies, this effect was also observed in 15-day-old heterozygous (+/-) mice, but it was not evident in 30-day-old and 2-year-old BACE1 KO (-/-) mice. Thus, BACE1 knockdown led to a transient decrease in NRG-1 processing in mice. Pharmacological inhibition of BACE1 in adult mice, which led to significant Abeta lowering, was without any significant effect on brain NRG-1 processing. Taken together, these results suggest that BACE1 is the major beta-site cleavage enzyme for APP and that its inhibition can lower brain Abeta and redirect APP processing via the potentially nonamyloidogenic alpha-secretase pathway, without significantly altering NRG-1 processing.

A key problem in engineering application of “design by analysis” approach is how to decompose a total stress field obtained by the finite element analysis into different stress categories defined in the ASME Code III and VIII-2. In this paper, we suggested an approach to separate primary stress with the principle of superposition, in which the structure does not need to be cut into primary structure but analyzed as a whole only with decomposed load. Taking pressurized cylindrical vessel with plate head as example, the approach is demonstrated and discussed in detail. The allowable load determined by the supposed method is a little conservative than that determined by limited load analysis.

Proteolysis of beta-amyloid precursor protein (APP) into amyloid beta peptide (Abeta) by beta- and gamma-secretases is a critical step in the pathogenesis of Alzheimer's Disease (AD), but the pathways regulating secretases are not fully characterized. Ubiquitinylation, which is dysregulated in AD, may affect APP processing. Here, we describe a screen for APP processing modulators using an siRNA library targeting 532 predicted ubiquitin ligases. Seven siRNA pools diminished Abeta production. Of these, siRNAs targeting PPIL2 (hCyp-60) suppressed beta-site cleavage. Knockdown of PPIL2 mRNA decreased BACE1 mRNA, while overexpression of PPIL2 cDNA enhanced BACE1 mRNA levels. Microarray analysis of PPIL2 or BACE1 knockdown indicated that genes affected by BACE1 knockdown are a subset of those dependent upon PPIL2; suggesting that BACE1 expression is downstream of PPIL2. The association of PPIL2 with BACE expression and its requirement for Abeta production suggests new approaches to discover disease modifying agents for AD.

Extracellular deposits of aggregated amyloid-beta (Abeta) peptides are a hallmark of Alzheimer disease; thus, inhibition of Abeta production and/or aggregation is an appealing strategy to thwart the onset and progression of this disease. The release of Abeta requires processing of the amyloid precursor protein (APP) by both beta- and gamma-secretase. Using an assay that incorporates full-length recombinant APP as a substrate for beta-secretase (BACE), we have identified a series of compounds that inhibit APP processing, but do not affect the cleavage of peptide substrates by BACE1. These molecules also inhibit the processing of APP and Abeta by BACE2 and selectively inhibit the production of Abeta(42) species by gamma-secretase in assays using CTF99. The compounds bind directly to APP, likely within the Abeta domain, and therefore, unlike previously described inhibitors of the secretase enzymes, their mechanism of action is mediated through APP. These studies demonstrate that APP binding agents can affect its processing through multiple pathways, providing proof of concept for novel strategies aimed at selectively modulating Abeta production.

Many real world problems have requirements and constraints which conflict with each other. One approach for dealing with such over-constrained problems is with constraint hierarchies. In the constraint hierarchy framework, constraints are classified into ranks, and appropriate solutions are selected using a comparator which takes into account the constraints and their ranks. In this paper, we present a local search solution to solving hierarchical constraint problems over finite domains (HCPs). This is an extension of local search for over-constrained integer programs WSAT(OIP) to constraint hierarchies and general finite domain constraints. The motivation for this work arose from solving large airport gate allocation problems. We show how gate allocation problems can be formulated as HCPs using typical gate allocation constraints. Using the gate allocation benchmarks, we investigate how constraint heirarchy selection strategies and the problem formulation using two models: a 0–1 linear constraint hierarchy model and a nonlinear finite domain constraint hierarchy model.

The amyloid beta peptides (Abeta) are the major components of the senile plaques characteristic of Alzheimer's disease. Abeta peptides are generated from the cleavage of amyloid precursor protein (APP) by beta- and gamma-secretases. Beta-secretase (BACE), a type-I transmembrane aspartyl protease, cleaves APP first to generate a 99-amino acid membrane-associated fragment (CT99) containing the N terminus of Abeta peptides. Gamma-secretase, a multi-protein complex, then cleaves within the transmembrane region of CT99 to generate the C termini of Abeta peptides. The production of Abeta peptides is, therefore, dependent on the activities of both BACE and gamma-secretase. The cleavage of APP by BACE is believed to be a prerequisite for gamma-secretase-mediated processing. In the present study, we provide evidence both in vitro and in cells that BACE-mediated cleavage between amino acid residues 34 and 35 (Abeta-34 site) in the Abeta region is dependent on gamma-secretase activity. In vitro, the Abeta-34 site is processed specifically by BACE1 and BACE2, but not by cathepsin D, a closely related aspartyl protease. Moreover, the cleavage of the Abeta-34 site by BACE1 or BACE2 occurred only when Abeta 1- 40 peptide, a gamma-secretase cleavage product, was used as substrate, not the non-cleaved CT99. In cells, overexpression of BACE1 or BACE2 dramatically increased the production of the Abeta 1-34 species. More importantly, the cellular production of Abeta 1-34 species induced by overexpression of BACE1 or BACE2 was blocked by a number of known gamma-secretase inhibitors in a concentration-dependent manner. These gamma-secretase inhibitors had no effect on enzymatic activity of BACE1 or BACE2 in vitro. Our data thus suggest that gamma-secretase cleavage of CT99 is a prerequisite for BACE-mediated processing at Abeta-34 site. Therefore, BACE and gamma-secretase activity can be mutually dependent.

This paper introduces the research on the Excitation Regulator of the Synchronous Generator with dual CPUs, based on Digital Signal Processor (TMS320LF2812). With the multiple functions of monitoring, analysis, controlling and protection, it overcomes the shortage of the domestic excitation device in terms of self-monitoring and self-protection，which effectively improves device reliability. By analyzing the allocation of reactive load of the interconnected Synchronous Motor group, the modeling and simulation of the digital excitation regulator in the power system are illustrated in the paper. The results of the simulation show that the proposed regulation model are feasible, satisfying various running demands of the Synchronous Motor and Power System.

This paper is concerned with the problem of camera distortion, and it presents a method with short computing time and high calibration accuracy, which can be easily achieved and adaptable to online distortion correction. By introducing adaptive iterative process this method could correct the camera distortion in real time. The method firstly applies the adaptive iterative process on the distortion model and corrects each feature points separately to get the distortion coefficients of each feature points. And then it utilizes the bilinear interpolation method and applies the corrected model on the distortion images. Finally, simulation results demonstrate the advantages of the proposed method.

A five-slab thick-plate model is developed to investigate the structural response of concrete pavements under vertical loads. The Reissner's thick-plate theory and the Winkler foundation model are employed in the derivation. Load transfer across joints between slabs is considered in the analysis. The solutions of the five-slab system are arrived at by superposing the solutions of three types of elemental plates. Numerical examples are presented to verify the results of the proposed model with those obtained by the finite element method.

beta-Secretase inhibition offers an exciting opportunity for therapeutic intervention in the progression of Alzheimer's disease. A series of isonicotinamides derived from traditional aspartyl protease transition state isostere inhibitors has been optimized to yield low nanomolar inhibitors with sufficient penetration across the blood-brain barrier to demonstrate beta-amyloid lowering in a murine model.

The effects of unilateral exposure to hypotonic media on the diffusional water permeability of the isolated rabbit conjunctiva were determined. For these experiments, a segment of the bulbar-palpebral conjunctiva was mounted between Ussing-type hemichambers under short-circuited conditions. Unidirectional diffusional water fluxes ( J dw ) were measured in either direction by adding 3 H 2 O to one hemichamber and sampling from the other. Electrical parameters were measured simultaneously. J dw were determined in control isosmotic conditions and after dilution of one of the bathing solutions from 290 to 108 mOsMolar. This hypotonic condition reduced J dw by 25–30% ( n =17) when applied basolaterally and by 25% ( n =6) apically. The effects were reversible and were also obtained when the opposite bathing solution contained amphotericin B, selectively permeabilizing the contralateral cell surface. From concomitant changes in transepithelial electrical resistance as well as 14 C-mannitol fluxes completed under identical conditions, arguments are presented that the above effect is best explained as a cell regulated reduction in membrane water permeability. Presumably both apical and basolateral membranes can down-regulate their water permeabilities. This response, suggesting a protective mechanism to help maintain cell volume from hypotonicity, was also seen in other studies using the amphibian bladder and the frog cornea, in which the effect was only obtained basolaterally. Thus, regulation of epithelial water permeability appears to be a basic trait common to both amphibians and mammals, although tissue differences exist.

SUMMARY In order to solve the contradictions that the static input–output table cannot be used for dynamic analysis, this paper unified the 2002, 2005, and 2007 input–output tables into 25 industries. Full energy intensity and embodied energy of China's export trade can be calculated quantitatively based on input–output analysis approach. We can get the time series data of 2001–2009 through the corrections of energy consumption per unit of gross domestic product, consumer price index, and exchange rate, and then analyze the trends of energy consumption of key industries. The results show that full energy intensity of China's 25 industries takes on downward trend generally, and the embodied energy of China's export trade is increased firstly and then has a downward trend. Processing trade had great impact on full energy intensity and embodied energy after deducting the processing trade; full energy intensity and embodied energy had decreased greatly. Smelting and pressing of metals, manufacture of chemicals, manufacture of communication equipment, computers, and other electronic equipment, and manufacture of textile are the largest energy-consuming industries of export trade in China. The trends of energy consumption in these four industries are similar to the total energy consumption; changes in export trade is the main reason for this result. Full energy intensity has a certain influence on the trend of energy consumption, but the effect is limited. Copyright © 2013 John Wiley & Sons, Ltd.

N1-guanyl-1,7-diaminoheptane (GC7) is a potent inhibitor of deoxyhypusine synthase (DHS), the enzyme that catalyzes the first step in the hypusination of eukaryotic translation initiation factor 5A (eIF-5A). Since eIF-5A is the only known cellular substrate for DHS and GC7 has been reported to block the proliferation of CHO cells, it has been suggested that DHS may be a novel target for anti-cancer therapy. In the present study we investigated the antiproliferative effect of GC7 on several tumorigenic cell lines under various growth conditions. We found that this compound inhibits the proliferation of H9 cells in suspension culture and the growth of HeLa cells and v-src-transformed NIH3T3 cells under both anchorage-dependent and anchorage-independent conditions. Moreover, studies with NIH3T3 cells and v-src-transformed NIH3T3 cells show that GC7 inhibits the growth of both cell lines in monolayer culture with similar potency and could not reverse the transformed phenotype. In addition, the v-src-transformed cells grown under both anchorage-dependent and anchorage-independent conditions showed similar sensitivity toward GC7. These data indicate that GC7 acts as a general antiproliferative agent and does not appear to preferentially target tumorigenic cell types. Cell cycle analysis show that GC7 reduces the CHO-K1 cell population in the G1-phase of the cell cycle by 42% and increases the number of cells in the S-phase by 44%. This cell cycle distribution profile strikingly resembles the distribution of cells treated with puromycin. This result supports the hypothesis that the synthesis of a subset of proteins important for the S-phase progression of CHO-K1 cells might be dependent upon hypusinated eIF-5A. Thus the antiproliferative effect of GC7 appears to be related to its interference with the progression of cell cycle, which also provides a possible explanation for the lack of selectivity of GC7 between nontransformed and transformed cell types tested in this study.

Treatment of Fura-2 loaded HEL cells, a human megakaryocyte-like cell line, with P2-purinoceptor nucleotide ligands (ADP, ATP, UTP, 2-methylthio-ATP) evoked a rise in cytosolic calcium. Homologous- and cross-desensitization studies using sequential addition of nucleotides showed that the ADP-induced calcium response in HEL cells was mediated mainly by purinoceptor(s) for which ADP but not ATP was an agonist. There were also minor contributions from purinoceptors for which ATP and ADP are both agonists (probably P2U and P2Y). ATP inhibited the ADP-induced calcium response in HEL cells. This inhibition was overcome by raising the ADP concentration, thus indicating that ATP was an antagonist for the HEL cell ADP receptor. AMP was also an antagonist, albeit weak, for the HEL cell ADP receptor. Antagonism of the ADP-induced calcium response by ATP was similarly observed in MEG-01 cells, another human megakaryocyte-like cell line, but not in 293 cells, a nonhematopoietic cell line. These studies suggest that HEL cells express an ADP receptor for which ATP and AMP are antagonists. This characteristic of the HEL cell ADP receptor is also displayed by the platelet P2T receptor. Thus, HEL cells appear to be a surrogate source of the platelet ADP receptor.

The bulbar-palpebral conjunctiva from albino rabbits was dissected as a cylinder and cut longitudinally to convert it to a flat epithelium that was mounted as a partition between Using-type chambers, exposing 0.38 cm2 of cross-sectional area. The tissue was bathed with a modified Tyrode's solution at 37 degrees C, pH 7.5. The tear-facing side (apical) was 14.6 +/- 1.5 mV negative relative to the basolateral side. Transepithelial resistance was 1.23 +/- 0.01 K omega.cm2 and the short-circuit current (Isc) was 14.4 +/- 1.3, microA/cm2. Sixty percent of the Isc could be accounted for by a Na(+)-dependent, bumetanide-inhibitable Cl- transport directed towards the apical side. The remainder of the Isc reflected a Na+ absorptive process at the apical surface that was amiloride resistant. Evidence was obtained that a likely contributor to this activity is an electrogenic Na(+)-glucose co-carrier. The Cl-dependent Isc was stimulated by forskolin and epinephrine. Permeabilization of the apical membrane with amphotericin B evinced a current carried by a basolateral Na+:K+ pump. An effect by heptanol suggested that part of the Isc traverse the epithelium via gap junctions. Our results imply that transport processes at the conjunctiva could influence the composition of the tear film.

Reduction in cerebrospinal fluid (CSF) amyloid β42 (Aβ42) and elevation in total tau and phospho-thr181 tau consistently differentiate between Alzheimer's disease (AD) and age-matched control subjects. In contrast, CSF β-site APP-cleaving enzyme activity (BACE1) and soluble amyloid precursor proteins α and β (sAPPα and sAPPβ) are without consistent patterns in AD subjects. Plasma sampling is much easier, with fewer side effects, and is readily applied in primary care centers, so we have developed and validated novel plasma BACE activity, sAPPβ, and sAPPα assays and investigated their ability to distinguish AD from age-matched controls. Plasma BACE activity assay was sensitive and specific, with signal being immunodepleted with a specific BACE1 antibody and inhibited with a BACE1-specific inhibitor. Plasma sAPPβ and sAPPα assays were specific, with signal diluting linearly, immunodepleted with specific antibodies, and at background levels in APP knockout mice. In rhesus monkeys, BACE1 but not γ-secretase inhibitor led to significant lowering of plasma sAPPβ with concurrent elevation of plasma sAPPα. AD subjects showed a significant increase in plasma BACE1 activity, sAPPβ, sAPPα, and Aβ42 (P < 0.001) compared with age-matched controls. In conclusion, plasma BACE activity and sAPP endpoints provide novel investigative biomarkers for AD diagnosis and potential pharmacodynamic biomarkers for secretase inhibitor studies.

In order to solve the contradictions that the static input-output table can't be used for dynamic analysis, this paper unified the 2002, 2005 and 2007 input-output tables into 25 industries, full energy intensity and embodied energy of China's export trade can be calculated quantitatively based on Input-Output analysis approach, we can get the time series data of 2001-2009 through the corrections of energy consumption per unit of GDP, consumer price index and exchange rate, and then analyze the trends of energy consumption of key industries. The results show that full energy intensity of China's 25 industries takes on downward trend generally and the embodied energy of China's export trade is increased firstly and then has a downward trend. Processing trade had great impact on full energy intensity and embodied energy, after deducting the processing trade; full energy intensity and embodied energy had decreased greatly. Smelting and Pressing of Metals, Manufacture of Chemicals, Manufacture of Communication Equipment, Computers and Other Electronic Equipment, Manufacture of Textile are the largest energy-consuming industries of export trade in China. The trends of energy consumption in these four industries are similar to the total energy consumption, changes in export trade is the main reason for this result, full energy intensity has a certain influence on the trend of energy consumption, but the effect is limited.

The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pKa of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Αβ production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5.

This Letter describes the one pot synthesis of tertiary carbinamine 3 and related analogs of brain penetrant BACE-1 inhibitors via the alkylation of the Schiff base intermediate 2. The methodology developed for this study provided a convenient and rapid means to explore the P1 region of these types of inhibitors, where the P1 group is installed in the final step using a one-pot two-step protocol. Further SAR studies led to the identification of 10 which is twofold more potent in vitro as compared to the lead compound. This inhibitor was characterized in a cisterna magna ported rhesus monkey model, where significant lowering of CSF Abeta40 was observed.

A role for endogenous dopamine in the control of rod and contributions to a second-order retinal neuron, the horizontal cell (HC) was studied in theXenopusretina. Relative rod and cone contributions were estimated from HC responses to scotopically balanced 491- and 650-nm flashes. In eyecups prepared in light then placed in darkness, cone input to the HC slowed and diminished on a time scale of hours. The decline in cone input was balanced by a slow growth of rod input to the HC. Administration of D-amphetamine, a dopamine releasing agent, restored the light-adapted waveform.The kinetics of slow light adaptation were examined by recording HC responses from eyecups that had been dark-adapted previously for 11–14 h. When test flashes fell on a dark field, cone input to the HC grew for 2–4 h, reached a plateau, and later declined. If, however, flashes were superimposed on a weak background field, cone input to the HC continued to increase monotonically at about 10%/h. This increase was abolished by superfusion with a nonspecific dopamine receptor blocker, cis-flupenthixol (50 μM), resulting in the complete suppression of cone-to-horizontal cell synaptic transfer and the enhancement of rod-to-horizontal cell communication. Subcutaneous injection of reserpine, a drug that depletes dopamine stores (2 mg/kg on 1–4 successive days), or intraocular injection of the dopamine neurotoxin, 6-hydroxydopamine (10–30 μg) slowed and reduced the amplitude of cone input to the HC, even in completely light-adapted eyes. Subsequent treatment with D-amphetamine (5–50 μM) or dopamine (10 μM) partially restored the normal response.Our experimental findings are consistent with the following hypothesis. Weak light is sufficient to stimulate dopamine release; dopamine augments cone-to-horizontal cell synaptic transfer and reduces rod-to-horizontal cell communication. The rapid kinetics of the fully light-adapted response depend on the presence of dopamine. Thus, dopamine appears to be an intraretinal signal for slow light adaptation.

To develop a novel cerebrospinal fluid (CSF) beta-secretase-1 activity assay and evaluate beta-secretase-1 (BACE-1) activity as a potential biomarker in human Alzheimer's disease.The assay consisted of an enzymatic reaction of CSF samples with an optimized beta-secretase peptide substrate and the cleavage products were detected using a neo-epitope specific antibody.The CSF BACE-1 activity assay described exhibits time, temperature, dose, and pH dependence, with sensitivity down to1 pM of recombinant BACE-1 enzyme, and is completely blocked by BACE-1 inhibitors. The endogenous BACE-1 enzyme in CSF appears to exist as a c-terminally truncated protein, based on both western blotting and capture-based activity assays. In a small cohort of human subjects, an age-dependent increase in CSF BACE activity was observed (~1.0 pM/year, p0.05). In Alzheimer's disease subjects, a significant decline in age-adjusted CSF BACE activity was observed compared to controls (56% in the log-transformed scale, p=0.02).We have developed a robust assay to measure CSF BACE-1 activity which could serve as a potential biomarker in human Alzheimer's disease subjects.

In two mung bean cultivars (Phaseolus raditus L. cv. 'Qindou-20' and 'Zhonglv-1') with different sensitivities to UV-B grown in growth chamber under supplemental or no supplemental UV-B radiation (0.4 W/m(2)) with or without 0.4% NaCl, the effects of NaCl stress on UV-B-induced DNA damage and repair were studied. The results showed that, under NaCl stress, (i) CPD accumulation was lower in the tolerant cultivar 'Zhonglv-1' but was the same in the sensitive cultivar 'Qindou-20', (ii) CPD formation in both cultivars was weakened, (iii) the photorepair and dark repair capacity were higher in the tolerant cultivar and (iv) the photorepair was weakened and dark repair capacity did not change in the sensitive cultivar. There was a negative correlation between susceptibility of CPD formation and levels of UV-absorbing compounds. These results demonstrate that NaCl stress can affect not only the susceptibility to CPD formation, but also the capacities for photorepair and dark repair of DNA, which together result in the change in UV-B-induced CPD accumulation and thereby that in sensitivity of plant to UV-B. The results also suggest that the differences in susceptibilities to CPD formation are due to the differences in levels of UV-absorbing compounds.

We describe the discovery and optimization of tertiary carbinamine derived inhibitors of the enzyme beta-secretase (BACE-1). These novel non-transition-state-derived ligands incorporate a single primary amine to interact with the catalytic aspartates of the target enzyme. Optimization of this series provided inhibitors with intrinsic and functional potency comparable to evolved transition state isostere derived inhibitors of BACE-1.

Rare familial forms of Alzheimer's disease (AD) are thought to be caused by elevated proteolytic production of the Aβ42 peptide from the β-amyloid-precursor protein (APP). Although the pathogenesis of the more common late-onset AD (LOAD) is not understood, BACE1, the protease that cleaves APP to generate the N terminus of Aβ42, is more active in patients with LOAD, suggesting that increased amyloid production processing might also contribute to the sporadic disease. Using high-throughput siRNA screening technology, we assessed 15,200 genes for their role in Aβ42 secretion and identified leucine-rich repeat transmembrane 3 ( LRRTM3 ) as a neuronal gene that promotes APP processing by BACE1. siRNAs targeting LRRTM3 inhibit the secretion of Aβ40, Aβ42, and sAPPβ, the N-terminal APP fragment produced by BACE1 cleavage, from cultured cells and primary neurons by up to 60%, whereas overexpression increases Aβ secretion. LRRTM3 is expressed nearly exclusively in the nervous system, including regions affected during AD, such as the dentate gyrus. Furthermore, LRRTM3 maps to a region of chromosome 10 linked to both LOAD and elevated plasma Aβ42, and is structurally similar to a family of neuronal receptors that includes the NOGO receptor, an inhibitor of neuronal regeneration and APP processing. Thus, LRRTM3 is a functional and positional candidate gene for AD, and, given its receptor-like structure and restricted expression, a potential therapeutic target.