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It is reported that quercetin (Que) can prevent tau pathology and induce neuroprotection by improving cognitive and functional symptoms in the treatment of Alzheimer’s disease (AD). However, its clinical application has been limited due to its poor brain targeting and bioavailability. Exosomes are considered as cargo carriers for intercellular communication and especially serve as a natural and important drug brain delivery platform for achieving better treatment of central neurological diseases. Here, we developed plasma exosomes (Exo) loaded with Que (Exo-Que) to improve the drug bioavailability, enhance the brain targeting of Que and potently ameliorate cognitive dysfunction in okadaic acid (OA)-induced AD mice. Our results showed that Exo-Que improved brain targeting of Que as well as significantly enhanced bioavailability of Que. Furthermore, compared with free Que, Exo-Que better relieved the symptoms of AD by inhibiting cyclin-dependent kinase 5 (CDK5)-mediated phosphorylation of Tau and reducing formation of insoluble neurofibrillary tangles (NFTs), suggesting its therapeutic potential for better treatment of AD.

The instability of organometal halide perovskites still remains a key obstacle restricting their practical application in gas sensing research. The first step in gas sensing using a semiconductor material is the recognition of a target gas through gas–solid interaction. In the current work, the adsorption mechanisms of MAPbI3–H2O, (MA)2Pb(SCN)2I2–H2O, (MA)2Pb(SCN)2I2–CH3COCH3, (MA)2Pb(SCN)2I2–NO2 and (MA)2Pb(SCN)2I2–O3 have been investigated by large-scale quantum dynamics simulations. The structural changes of the perovskite skeleton, the adsorption energy, and the charge transfer between the semiconductor material and the gas molecules have been analysed. The suitability and effectiveness of quantum dynamics simulations in adsorption mechanism research are firstly validated by comparing the humidity sensing mechanisms of MAPbI3 and (MA)2Pb(SCN)2I2. Different sensing mechanisms of (MA)2Pb(SCN)2I2 to gases with different oxidising properties have been proposed. These sensing mechanisms hopefully lay a foundation for the development of novel perovskite gas sensing materials with enhanced stability, high sensitivity, and high selectivity.

A smart meta-superconductor Bi(Pb)SrCaCuO (B(P)SCCO) may increase the critical transition temperature (TC) of B(P)SCCO by electroluminescence (EL) energy injection of inhomogeneous phases. However, the increase amplitude ΔTC (ΔTC=TC−TC,pure) of TC is relatively small. In this study, a smart meta-superconductor B(P)SCCO with different matrix sizes was designed. Three kinds of raw materials with different particle sizes were used, and different series of Y2O3:Sm3+, Y2O3, Y2O3:Eu3+, and Y2O3:Eu3++Ag-doped samples and pure B(P)SCCO were prepared. Results indicated that the TC of the Y2O3 or Y2O3:Sm3+ non-luminescent dopant doping sample is lower than that of pure B(P)SCCO. However, the TC of the Y2O3:Eu3++Ag or Y2O3:Eu3+ luminescent inhomogeneous phase doping sample is higher than that of pure B(P)SCCO. With the decrease of the raw material particle size from 30 to 5 μm, the particle size of the B(P)SCCO superconducting matrix in the prepared samples decreases, and the doping content of the Y2O3:Eu3++Ag or Y2O3:Eu3+ increases from 0.2% to 0.4%. Meanwhile, the increase of the inhomogeneous phase content enhances the ΔTC. When the particle size of raw material is 5 μm, the doping concentration of the luminescent inhomogeneous phase can be increased to 0.4%. At this time, the zero-resistance temperature and onset transition temperature of the Y2O3:Eu3++Ag doped sample are 4 and 6.3 K higher than those of pure B(P)SCCO, respectively.

As a traditional Chinese medicine, Salvia miltiorrhiza rhizome is mainly used to treat cardiovascular diseases. Symbiosis of endophytic fungi with their host plants, is an effectively regulatory means to promote the growth and secondary metabolism of medicinal plants. Here, an endophytic fungus Mucor circinelloides DF20 was co-cultivated with the sterile seedlings of S. miltiorrhiza, to clarify the promoting mechanism on tanshinone biosynthesis and accumulation in S. miltiorrhiza root. The assay of promoting-growth activities in vitro showed that DF20 have the ability to produce IAA and siderophores. DF20 could significantly promote the biosynthesis and accumulation of tanshinones in the root of S. miltiorrhiza, especially the content of tanshinone ⅡA, reaching 4.630 ± 0.342 mg/g after 56 days of DF20 treatment, which is 22-fold of the control group. The result also showed that the hyphae of M. circunelloides DF20 mainly colonized in the root tissue interspace of S. miltiorrhiza, and a small amount of hyphae were located inside the cells. The results of florescent real-time quantitative RT-PCR showed that DF20 colonization significantly increase the expression level of some key enzyme genes (DXS, DXR, HMGR, GGPPS) in tanshinone biosynthesis pathway, but the regulatory effect mainly occurred in the early stage of co-culture, while the expression level decreased in different degrees in the later stage. In conclusion, the endophytic fungus M. circunelloides DF20 can form an interaction relationship with its host, then to promote the biosynthesis and accumulation of tanshinones in root by upregulating the key enzyme genes expression levels of the biosynthesis pathway.

Arguments regarding the biocompatibility of graphene-based materials (GBMs) have never ceased. Particularly, the genotoxicity (e.g., DNA damage) of GBMs has been considered the greatest risk to healthy cells. Detailed genotoxicity studies of GBMs are necessary and essential. Herein, we present our recent studies on the genotoxicity of most widely used GBMs such as graphene oxide (GO) and the chemically reduced graphene oxide (RGO) toward human retinal pigment epithelium (RPE) cells. The genotoxicity of GO and RGOs against ARPE-19 (a typical RPE cell line) cells was investigated using the alkaline comet assay, the expression level of phosphorylated p53 determined via Western blots, and the release level of reactive oxygen species (ROS). Our results suggested that both GO and RGOs induced ROS-dependent DNA damage. However, the DNA damage was enhanced following the reduction of the saturated C–O bonds in GO, suggesting that surface oxygen-containing groups played essential roles in the reduced genotoxicity of graphene and had the potential possibility to reduce the toxicity of GBMs via chemical modification.

To investigate the effects of different types and concentrations of organic matter on anaerobic ammonium oxidation (anammox), the effects of short-term stresses induced by organic matter on...

The EtOH extract of the roots of Platycodon grandiflorum afforded two new triterpene saponins platycoside P (1) and platycoside Q (2). Their structures were elucidated based on spectroscopic means and hydrolysis products. These compounds were evaluated for inhibitory activity against LPS-induced TNF-α production in RAW 246.7 macrophages. Compounds 1 and 2 showed inhibitory activity with the inhibition ratios (%) of 38.6 and 44.1 at 50 μM, respectively.

Alzheimer's disease (AD) is a common neurodegenerative disease of the central nervous system. Due to its complex pathogenesis and the difficulty of drugs to cross the blood brain barrier (BBB), no effective clinical drugs are currently available that prevent the development of the course of AD. Silibinin (Slb) is known to exert dual therapeutic effects on reducing amyloid-β (Aβ) aggregation and deactivating astrocytes to improve behaviour and cognitive performance in subjects with Alzheimer's disease (AD). However, the poor brain targeting ability and low bioavailability limit its wide application. We aimed to encapsulate Slb in macrophage-derived exosomes (Exo-Slb) to improve its brain targeting ability. After entering the brain, exosomal Slb selectively interacted with Aβ monomers to reduce its aggregation. At the same time, Exo-Slb was internalized in astrocytes to inhibit their activation and alleviate astrocyte inflammation-mediated neuronal damage. Finally, Exo-Slb potently ameliorated cognitive deficits in AD mice.

Alumina ceramics with good mechanical and corrosion resistance, is one of the most widely used engineering ceramics. The aluminum has a high strength, high conductivity, high plasticity, etc. than aluminum ceramics used in more and more industries. In this paper, aluminum and alumina powder as raw material, mixing, forming, sintering and a series of processes for preparing the alumina/aluminum metallic ceramic materials, through performance testing and analysis can be found in the ratio of raw materials 50wt% Al, 50wt % Al2O3 relatively good moldability. After sintering, after measuring the density contrast is found better density in the pressing process pressure of 20MPa and holding pressure time for 20min. By comparing the sintering process, after the interface structure by scanning electron microscopy and found help improve density through the secondary sintering metallic ceramic materials.

Limited oxygenation and over-oxidation experiments were designed to compare the phenolic and chromatic characters of base wines Cabernet Franc (CF), Cabernet Sauvignon (CS), and their counterparts that blended with modifier wines Marselan (MA) and Petit Verdot (PV). In both limited oxygenation and over-oxidation conditions, all blend wines generally contained higher C*ab, a* and Red%, and lower hab, b* and Yellow% than their base wine counterparts, because MA contributed flavonols (copigments) and anthocyanins, and PV contributed flavanols (anthocyanin derived pigments precursors). Chromatic changes that can be perceived by human eye (ΔE*ab) in CF based blend wines were more obvious than that of CS based blend wines, which indicate that base wine with lower phenolic concentrations and weak phenolic profiles (CF) might be more prone to be chromatically modified than base wine with higher phenolic concentrations and distinct phenolic profiles (CS). Chemical influences of different blending strategies on anthocyanin derivatives' formations were depending on phenolic profiles of the modifier wines and base wines, and also on the oxygen exposure. The results suggest that the chromatic improvement of base wines could be realized by blending modifier wines under different oxygen exposures.

Effects of different C/N (NO2–N) ratios on nitrogen removal and microbial community structure were investigated using an anaerobic baffled reactor (ABR). Results indicated that the C/N ratio exerted an important effect on nitrogen removal in the anammox-coupling-denitrification process associated with the ABR. When the C/N ratio was 1.29, the ABR could achieve the highest total nitrogen (TN) removal efficiency of 99.9%. Most of TN was removed in the 1st and 2nd compartment, accounting for about 81.0–97.6% of total TN removal. The nitrogen removal resulted from the interaction among anammox, heterotrophic denitrificans, and other microbes within the ABR. The contribution of anammox to nitrogen removal varied from 6.8% to 32.4%. High-throughput MiSeq sequencing analyses revealed that the C/N ratio was one of the most important factors regulating the microbial community structure, and the predominant phylum changed from Proteobacteria to Chloroflexi with the elevated C/N ratio. In addition, the Candidatus Brocadia was the major anammox bacterium, and its percentage varied from 1.0–2.9% at day 9 to 2.8–9.1% at day 46.

N-doped porous carbons (NPCs) are highly promising for CO2 capture, but their preparation is severely hindered by two factors, namely, the high cost of N-containing polymer precursors and the low yield of carbon products. Here we report for the first time the fabrication of NPCs through the rational choice of the polymer NUT-4, with low cost and high phenyl density, as precursor. For the material NPC-600 obtained from carbonization at 600°C, the yield is as high as 52.1%. The adsorption capacity of CO2 on NPC-600 reaches 6.9 mmol/g at 273 K and 1 bar, which is obviously higher than that on the benchmarks, including 13X zeolite (4.1 mmol/g) and activated carbon (2.8 mmol/g), as well as most reported carbon materials. Our results also demonstrate that the present NPCs can be completely regenerated under mild conditions. The abundant microporosity and “CO2-philic” (N-doped) sites are responsible for the adsorption performance. This article is protected by copyright. All rights reserved.

Cermet while maintaining the excellent properties of ceramic materials, but also have the advantages of a metal material, is an important new engineering materials. In this paper, prepared by calcination of alumina - aluminum metal-ceramic composite material powder, and its characterization as a basis to provide raw materials for preparing high performance metal ceramic material. According to the research, with the calcination temperature is increased, the rate of change gradually increase the weight of aluminum. Calcined at a temperature of 600¡æ, the oxidation of aluminum surface the best. With the firing time increases, the rate of change in the weight of aluminum powder showed an increasing trend. When 8h, oxidation of aluminum surface better. Through this experiment, process optimization can be found in the calcination temperature was 600¡æ, calcination time is 8h, the best coating effect aluminum surface, coating evenly, clean interface, the reaction layer thickness of about 700nm, the prepared package type composite powders the best results.

Metal ceramics are a important new engineering materials with the advantages of ceramics and metal materials. The Al-Al2O3 metal ceramics were prepared via the powder metallurgy methods and characterized in this paper, which lay the base for preparing the high performance cermet materials. Through the results and analysis, the conclusions are shown that the relative density is increased with a increasing forming pressure, the electrical resistivity is decreased with a increasing forming pressure. The relative density is increased with a increasing sintering temperature under 700°C, the relative density decreases with a increasing sintering temperature above 700°C, the electrical resistivity is shown the opposite tendency. Through the optimizing the technological parameter, such as the sintering temperature at 700°C, the forming pressure under 20MPa, the Al content for 75wt%, Al-Al2O3 metal ceramics are successfully prepared with the high relative density and the low electrical resistivity, the relative density is 97.52%, and the electrical resistivity is 101.34Ω·m

Back-channel-etch-structured thin-film transistors (TFTs) employing amorphous Indium-Gallium-Zinc-Tin-Oxide (IGZTO) and Mo/Al as active layer and source/drain, respectively, were demonstrated with good electronic property and bias-temperature-stress stability. LCD panels addressed by such TFTs with gate-driver-on-array circuit passed the 1000- hour high-temperature-operating and high-temperature/humidity-operating reliability tests, revealing excellent prospect for mass-production.

With the expansion of greenhouse vegetable production, secondary soil salinization and CO2 deficits have emerged as major handicaps that seriously affect the yield and quality of tomatoes. To explore the effects of CO2 enrichment on Ca(NO3)2 that generates the major cations (Ca2+) and anions (NO3–) responsible for secondary salinization in protected vegetable production, the tomato cultivar 'Zhong za 9′ was exposed to 800 μmol/mol CO2 and 80 mmol/L Ca(NO3)2 for seven days, and their effects on the growth and physiological characteristics were examined. Enrichment with CO2 significantly promoted the net photosynthetic rate and biomass accumulation, alleviated the oxidative damage caused by salt stress, and improved the ion homeostasis under Ca(NO3)2 stress. CO2 enrichment also reduced the electrolyte leakage, malondialdehyde, superoxide anion, and hydrogen peroxide concentrations by increasing the activity of antioxidant enzymes such as superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT). Elevated CO2 also differentially modulated the free amino acid concentrations and endogenous polyamine inter-conversion under salt stress, which improved the tolerance of plants to Ca(NO3)2 stress. Our results suggest that CO2 enrichment can effectively alleviate the damage of tomato seedlings caused by Ca(NO3)2 stress, and it can be considered as a feasible strategy to manage secondary salinization in protected vegetable production.

Phosphate (Pi) is often one of the limiting nutrients for plants in soil. Long-term low inorganic phosphate causes irreversible damage to plant cells and limits plant growth. Plants have evolved a series of adaptive responses to circumvent the potential damaging effects of low-Pi stress on living, such as biochemical, physiological and developmental changes. However, the research on the response of photosynthetic organelle to low-Pi stress is scarce. In this research, we investigated the responses of photosynthetic organelle to low-Pi by means of physiological and biochemical analysis. The results indicated that the growth of melon seedling was hampered and dry matter accumulation reduced by low-Pi stress. Low-Pi stress compelled the light intercepted excessive for melon’s actual processing capacity, thereby leading to the reduction of net photosynthesis. The relative electron transport rates and actual quantum yield of photo system were significantly decreased by low-Pi stress with analyzing the chlorophyll fluorescence data. To mitigate the photo inhibition, melon started up the non-photochemical quenching of chlorophyll fluorescence (NPQ) to dissipating excess excitation energy. Meanwhile, low-Pi disrupted the normal photosynthetic electron transport pattern by inhibiting cyclic and non-cyclic electron transport, promoting pseudo-ring electron transport, thus leading to reactive oxygen production in leaves. The reactive oxygen scavenging enzymes activity analysis revealed that the activity was significantly improved by low-Pi to counterbalance the deleterious effects of reactive oxygen species. However, the malondialdehyde content and less developed membrane system of thylakoid observed from ultrastructural chloroplast indicated that these mechanisms failed to keep redox homeostasis and leaves suffered from photo-oxidative stress symptoms. Based on these experimental results we concluded that low-Pi inhibited the activity of photosyetem and further caused photo-oxidative stress and photo inhibition. To alleviate the negative effect, NPQ mechanism, alternative electron transport pathways and antioxidant system were activated to protect the photosynthetic organelles.

Owing to their high physicochemical stability and low skeleton density, polymers are highly promising for capturing the greenhouse gas CO2. However, complicated monomers, expensive catalysts, and/or severe conditions are usually required for their synthesis, which makes the process costly, tedious, and hard to scale up. In this paper, a facile nucleophilic substitution reaction is developed to synthesize polymers from low-cost monomers, namely chloromethylbenzene and various diamines. Due to the appropriate reactivity of monomers, the polymerization takes place at a low temperature of about 60 °C in the absence of any catalysts. A series of polymers containing plentiful secondary amines are successfully fabricated; these secondary amines provide a proper adsorbate–adsorbent interaction from the viewpoints of selective capture of CO2 and energy-efficient regeneration of adsorbents. Moreover, the materials possess well-defined micropores with the dimension close to the size of adsorbate molecules and subseq...

Diamond was done on sintered tungsten block with or without sputtered tungsten films. The effects of various depositing conditions, including methane concentration, temperature, pressure, the diamond seeding step and reaction time, on diamond growth were investigated in detail. The results show that the sputtered tungsten film has a dual effect on diamond growth. Firstly, after ultrasonication with diamond slurry, the tungsten film will adsorb a large number of diamond nanoparticles. Therefore, the nucleation density of diamond will be substantially improved. Secondly, the film will be carbonized during the deposition process and the carbon on the surface of the film will decrease. Methane concentration generally does not affect the carbonization level of the tungsten film but higher temperature will lead to a higher level of carbonization. The carbonization process of sputtered tungsten films during deposition is made up of two steps. Also, the nucleation surface of diamond was revealed. The nucleation surface was a layer of ultrasmooth and seamless nanocrystalline diamond film with high-quality and special surface architecture (tiny peaks arrays), which is potential to be applied in MEMS and field-emission devices. A potential method to prepare ultrasmooth nanocrystalline diamond films is proposed.

The insulator-metal transition triggered by pressure in charge transfer insulator NiS2 is investigated by combining high-pressure electrical transport, synchrotron x-ray diffraction and Raman spectroscopy measurements up to 40–50 GPa. Upon compression, we show that the metallization firstly appears in the low temperature region at ∼3.2 GPa and then extends to room temperature at ∼8.0 GPa. During the insulator-metal transition, the bond length of S–S dimer extracted from the synchrotron x-ray diffraction increases with pressure, which is supported by the observation of abnormal red-shift of the Raman modes between 3.2 and 7.1 GPa. Considering the decreasing bonding-antibonding splitting due to the expansion of S–S dimer, the charge gap between the S-ppπ* band and the upper Hubbard band of Ni-3d e g state is remarkably decreased. These results consistently indicate that the elongated S–S dimer plays a predominant role in the insulator-metal transition under high pressure, even though the p-d hybridization is enhanced simultaneously, in accordance with a scenario of charge-gap-controlled type.

Selective reduction of supported CuO to Cu2O was realized using the strategy of vapor-induced reduction, in which HCHO/H2O vapor diffuses into the pores of the support and interacts with predispersed CuO. This new strategy allows the fabrication of supported cuprous sites at much lower temperatures within a short time, avoids the formation of Cu(0) with a Cu(I) yield of nearly 100%, and results in materials with good adsorption performance, which is impossible to achieve by conventional methods.

This study presents a novel and rapid method to identify chemical markers for the quality control of Radix Aconiti Preparata, a world widely used traditional herbal medicine. In the method, the samples with a fast extraction procedure were analyzed using direct analysis in real time mass spectrometry (DART MS) combined with multivariate data analysis. At present, the quality assessment approach of Radix Aconiti Preparata was based on the two processing methods recorded in Chinese Pharmacopoeia for the purpose of reducing the toxicity of Radix Aconiti and ensuring its clinical therapeutic efficacy. In order to ensure the safety and effectivity in clinical use, the processing degree of Radix Aconiti should be well controlled and assessed. In the paper, hierarchical cluster analysis and principal component analysis were performed to evaluate the DART MS data of Radix Aconiti Preparata samples in different processing times. The results showed that the well processed Radix Aconiti Preparata, unqualified processed and the raw Radix Aconiti could be clustered reasonably corresponding to their constituents. The loading plot shows that the main chemical markers having the most influence on the discrimination amongst the qualified and unqualified samples were mainly some monoester diterpenoid aconitines and diester diterpenoid aconitines, i.e. benzoylmesaconine, hypaconitine, mesaconitine, neoline, benzoylhypaconine, benzoylaconine, fuziline, aconitine and 10-OH-mesaconitine. The established DART MS approach in combination with multivariate data analysis provides a very flexible and reliable method for quality assessment of toxic herbal medicine.

The structural and electronic properties of a hydrogen terminated hexagonally AlN nanoribbon with 6 zigzag Al–N chains across the ribbon width (6-ZAlNNR) and the hexagonally bonded hetero-sheets AlNCx ( x = 2 , 4 , 6 ) consisting of AlN and graphite strips with zigzag shaped borders have been investigated systemically by using the first-principles. The results show that in 6-ZAlNNR, the states of the lowest unoccupied conduction band (LUCB) and the highest occupied valence band (HOVB) at zone boundary Z are edge states whose charges are localized at edge Al and N atoms, respectively. Introducing the graphite strip Cx and increasing its width lead to the LUCB and HOVB getting closer with each other especially in flat dispersion region around the zone boundary Jy, thus decreasing in the energy gap of the hetero-sheets AlNC2, AlNC4 and AlNC6 successively. Similar to the edge states existing in zigzag edged AlNNR, the flat dispersion border states also exist in the zigzag borders of hexagonally networked hetero-sheets AlNCx. Unlike the edge states whose charges are localized at one of the edge atoms, the border states are localized at two atoms of the borders with either bonding or antibonding character.

We have shown previously that glycyrol has an inhibitory effect on the immune response in mice by reducing calcineurin activity (Li et al., 2010, Pharm Biol 48:1177–1184). Here, we investigated the interaction of glycyrol with calcineurin A (CNA, catalytic A subunit of calcineurin) by spectroscopic methods and docking. We showed that glycyrol binds to CNA via hydrophobic interactions in a ratio of 1:1, and the main binding site is in the catalytic domain of CNA close to the calcineurin B subunit-binding domain. Binding of glycyrol changes the secondary structure of CNA, and this effect may possibly inhibit CN activity. © 2011 IUBMB IUBMB Life, 63(1): 14–20, 2011

Kaempferol, in our previous study, was a new immunosuppressant on calcineurin (CN), the Ca(2+)/calmodulin (CaM)-dependent protein phosphatase. Here, we examined the interactions of kaempferol with CN by fluorescence spectroscopy (FS), circular dichroism spectroscopy (CD) and docking. Data of kaempferol with CN catalytic subunit (CN A) and its truncated mutant CNAa obtained by FS method showed that the binding stoichiometry of kaempferol/CN A was 1:1, catalytic domain of CN A was the concrete domain for kaempferol binding while other domains contributed a lot to this binding. Distances from kaempferol to each tryptophan (Trp) in CN A by energy transfer experiments and the subsequent docking study interestingly provided the same binding sites for kaempferol, which all located in the non-active site area of CN A catalytic domain, also consisted with our previous conclusion from CN activity assay. Furthermore, CD results showed a much tighter structure of CN A for the inhibitor binding; on the other hand, presence of Ca(2+) and Mn(2+) decreased kaempferol binding on CN A.

Hot compressive deformation of Ti600 alloy after thermo hydrogen treatment (THT) was carried out within hydrogen content range of 0–0.5%, temperature range of 760–920 °C and strain rate range of 0.01–10 s−1. The flow stress of Ti600 alloy after THT was obtained under hot deformation condition, and the influence of hydrogen on work-hardening rate (S*), strain energy density (U*), and deformation activation energy (Q) was analysed. The results show that the flow stress of Ti600 alloy decreases remarkably with the increase of hydrogen when the hydrogen content is less than 0.3%. Both S* and U* decrease with the increase of hydrogen when the hydrogen content is less than 0.3%, and when the hydrogen content is more than 0.3%, S* and U* increase with hydrogen addition. The value of Q decreases with the increase of strain at the same hydrogen content. The addition of small quantity of hydrogen leads to an increase of Q at small strain values, and when the strain reaches 0.6, the value of Q decreases gradually with the increase of hydrogen. When the hydrogen content is within the range of 0.1%–0.3%, the flow stress of Ti600 alloy is decreased when being deformed at the temperature range of 760–920 °C.

The microstructures of Ti6Al4V alloy after hydrogenation were investigated by optical microscopy(OM), X-ray diffraction(XRD) and transmission electron microscopy(TEM). The influence of hydrogenation on the hardness of α and β phases was analysed by microhardness testing. The influence of hydrogenation on alloying elements diffusion was studied by electron probe microanalysis(EPMA). The microstructural observation reveals that hydride δ (FCC structure) as well as large number of dislocations precipitate in the specimens with 0.278% and 0.514% hydrogen, and a lot of twins are found in the specimen with 0.514% hydrogen, simultaneously. The result of microhardness testing shows that the hardness of α and β phases increases synchronously with the increase of hydrogen and the hardness increment of β is larger than that of α. According to analysis of EPMA, the diffusion ability of alloy elements Al and V increases after hydrogenation. It is considered that hydrogen solution strengthening and V element diffusion are the main factors causing the hardness of α phase increase with the increase of hydrogen, and the formation of δ hydrides, lattice defects, hydrogen solution strengthening and Al element diffusion jointly cause the hardness of β phase increase with the increasing hydrogen.

Basic peptides such as human immunodeficiency virus type 1 (HIV-1) Tat-(48-60) and Drosophila Antennapedia-(43-58) have been reported to have a membrane permeability and a carrier function for intracellular protein delivery. Based on the fluorescence microscopic observations of the vascular endothelial cells (ECV-304) and the primary cultured neuroglial cells, we found that human Clock protein DNA-binding peptide [residue 35-47, hClock-(35-47)] had a translocation activity very similar to Tat-(48-60). The cellular uptake of hClock-(35-47) increases with the increase of incubation time and concentration. The internalization effect at 4 degrees was same as that at 37 degrees C. Internalization of hClock-(35-47) was saturable and could be inhibited by the excess of the other MPPs. Moreover, the uptake of these peptides were significantly inhibited in the presence of heparan sulfate. These results strongly suggested that the hClock-(35-47) shared a common or very similar internalization pathway with other MPPs. Furthermore, we injected rat through the common carotid artery with hClock-(35-47)-FITC peptide, and cryostat sections of the brain were prepared and observed using a fluorescence microscope. Result showed that the peptide had the ability to translocate through the blood-brain barrier. It is promising to provide a new safe carrier for the intracellular and encephalic treatment.

Porous polymer networks have great potential in various applications including carbon capture. However, complex monomers and/or expensive catalysts are commonly used for their synthesis, which makes the process complicated, costly, and hard to scale up. Herein, we develop a molecular template strategy to fabricate new porous polymer networks by a simple nucleophilic substitution reaction of two low-cost monomers (i.e., chloromethylbenzene and ethylene diamine). The polymerization reactions can take place under mild conditions in the absence of any catalysts. The resultant materials are interconnected with secondary amines and show well-defined micropores due to the structure-directing role of solvent molecules. These properties make our materials highly efficient for selective CO2 capture, and unusually high CO2/N2 and CO2/CH4 selectivities are obtained. Furthermore, the adsorbents can be completely regenerated under mild conditions. Our materials may provide promising candidates for selective capture of CO2 from mixtures such as flue gas and natural gas.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory and autoimmune disease accompanied by the destruction and deformities of joints. Adjuvant-induced arthritis (AIA) is one of the excellent animal models of RA used to understand disease pathogenesis and screen potential drugs. In this paper, a urinary metabonomics method based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) has been established to investigate the disease progression of AIA and find potential biomarkers of secondary inflammation in AIA rats. 24 potential biomarkers were identified, including xanthurenic acid, kynurenic acid, 4-pyridoxic acid, and phenylalanine, which revealed that tryptophan metabolism, phenylalanine metabolism, gut microbiota metabolism and energy metabolism were disturbed in AIA rats. These potential biomarkers and their corresponding pathways are helpful to further understand the mechanisms of AIA and pathogenesis of RA. This study demonstrates that metabonomics based on UPLC-Q-TOF-MS is a powerful methodology to analyze the underlying disease pathogenesis.

After birth, the full-term ductus arteriosus actively constricts and undergoes extensive histologic changes that prevent subsequent reopening. These changes are thought to occur only if a region of intense hypoxia develops within the ductus wall after the initial active constriction. In preterm infants, indomethacin-induced constriction of the ductus is often transient and is followed by reopening. Prostaglandins and nitric oxide both play a role in inhibiting ductus closure in vitro. We hypothesized that combined inhibition of both prostaglandin and nitric oxide production (with indomethacin and N-nitro-L-arginine (L-NA), respectively) may be required to produce the degree of functional closure that is needed to cause intense hypoxia. We used preterm (0.67 gestation) newborn baboons that were mechanically ventilated for 6 d: 6 received indomethacin alone, 7 received indomethacin plus L-NA, and 16 received no treatment (control). Just before necropsy, only 25% of control ductus and 33% of indomethacin-treated ductus were closed on Doppler examination; in contrast, 100% of the indomethacin-plus-L-NA-treated ductus were closed. Control and indomethacin-treated baboons developed negligible-to-mild ductus hypoxia (EF5 technique). Similarly, there was minimal evidence of ductus remodeling. In contrast, indomethacin-plus-L-NA-treated baboons developed intense hypoxia in regions where the ductus was most constricted. The hypoxic muscle strongly expressed vascular endothelial growth factor, and proliferating luminal endothelial cells filled and occluded the lumen. In addition, cells in the most hypoxic regions were undergoing DNA fragmentation. In conclusion, preterm newborns are capable of remodeling their ductus, just like the full-term newborn, if they can reduce their luminal blood flow to a point that produces intense ductus wall hypoxia. Combined prostaglandin and nitric oxide inhibition may be necessary to produce permanent closure of the ductus and prevent reopening in preterm infants.

A urinary metabonomics method based on the ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) had been established to investigate the holistic efficacy of Wu-tou decoction (WTD), a traditional Chinese medicine (TCM) formula used to treat rheumatoid arthritis (RA), in adjuvant-induced arthritis (AIA) rat model. Multivariate statistical approaches, such as principal component analysis (PCA) and orthogonal projection to latent structures squares-discriminant analysis (OPLS-DA) were used to distinguish healthy control group, AIA model group and WTD treated group and find potential biomarkers. There was a clear separation among the three groups in PCA model. Sixteen potential biomarkers had been identified using OPLS-DA, and 11 of them was considered to be in response to therapeutic effects of WTD involved in tryptophan metabolism, phenylalanine metabolism, tricarboxylic acid (TCA) cycle, bile acid biosynthesis, steroid hormone biosynthesis and valine metabolism. In this study, WTD also showed good anti-inflammatory and antioxidant activities in vivo, and it could suppress histopathological changes of AIA rats. There might be a correlation between these results and the regulation of the disturbed metabolites in urine. This study demonstrates that metabonomics is a powerful methodology to gain insight in the mechanism of TCM formula in therapy.

Regulation of ductus arteriosus (DA) tension depends on a balance between oxygen-induced constriction and PG and nitric oxide (NO)-mediated relaxation. After birth, increasing PaO2 produces DA constriction. However, as the full-term ductus constricts, it develops severe tissue hypoxia in its inner vessel wall (oxygen concentration 0.2%, endogenous PGs and NO inhibit more than 40% of the active tension developed by the ductus. However, when tissue oxygen concentrations drop below 0.2%, the constitutive relaxation of the ductus by endogenous PGs and NO is lost. In the absence of PG and NO production, tension increases to a level normally observed only after treatment of the ductus with indomethacin and nitro-l-arginine methyl ester (inhibitors of PG and NO production). Therefore, under conditions of severe hypoxia (tissue oxygen concentration

Because thrombin-treated tumor cell-induced metastasis increases tumor nodule volume12 greater than nodule number, we studied the effect of thrombin on tumor cell growth in vitro and in vivo (murine B16F10 melanoma, human HCT8 colon carcinoma, DU145 prostate carcinoma). Tumor cell growth was measured after 3 to 7 days in 1% fetal calf serum (FCS) + RPMI 1640. We found that, whereas relatively low concentrations of thrombin, 0.1 to 0.5 U/mL (1-5 nmol/L) enhance tumor cell growth in vitro approximately 2- to 3-fold, higher concentrations, 0.5 to 1 U/mL (5-10 nmol/L) impaired cell growth approximately 2- to 4-fold. Impaired cell growth was associated with cell cycle arrest at G2M and increased pre-GoDNA, as well as apoptosis, measured by tumor cell binding to Annexin V and propidium iodide. Apoptosis was reversed with the general caspase inhibitor, FK-011. The enhancing and inhibiting effects were specific for thrombin (reversed with inactive diisopropyl-fluorophosphate [DFP]-thrombin) and mediated via the protease-activated receptor 1 (PAR-1). PAR-1 activation was demonstrated by (1) use of a cell line, B16F10, devoid of the 3 other thrombin receptors, PAR-3, PAR-4, and GPIb; and (2) greater sensitivity of PAR-1 transfected B16F10 and HCT8 cells to impaired cell growth/apoptosis, 3- and 14-fold, respectively. Thus, thrombin has a bimodal effect on PAR-1 in tumor cells: enhanced growth at low concentration, impaired growth/apoptosis at higher concentration.

Angiopoietin-1 (Ang-1) is required for developing vessels, and its absence leads to defects in vessel remodeling. Ang-1 has been identified as the ligand for the tyrosine kinase receptor Tie-2, which is expressed specifically on endothelial cells and early hematopoietic cells. In studying the role of Tie-2 and Ang-1 in megakaryocytopoiesis, 3 alternatively spliced species of Ang-1 mRNA (Ang-1.3 kb, Ang-0.9 kb, and Ang-0.7 kb) were identified in addition to the full-length Ang-1 (Ang-1.5 kb), in the megakaryocyte cell line CHRF by reverse transcription–polymerase chain reaction (RT-PCR), and then cloned and sequenced. The expression of 3 alternatively spliced isoforms of Ang-1 was confirmed by RT-PCR using specific primer pairs derived from junction sites and the 3′ end of Ang-1 cDNA, and it was further demonstrated by nuclease protection assay, Northern blotting, and immunoblotting in CHRF cells. Expression of the Ang-1.3 kb isoform was also detected in human primary fibroblast cell line FS4, breast cancer cell line MDAMB-468, and CD34+CD41+ cells of fetal liver and platelets. The function of the 1.5-kb, 1.3-kb, and 0.9-kb isoforms was examined. Recombinant proteins Ang-1.5 and 0.9 kb bind strongly to the recombinant Tie-2 receptor (Tie-2-Fc), whereas the 1.3-kb isoform does not. The Ang-1.3 kb isoform binds to the 1.5-kb isoform. Ang-1.5 kb, but not the 1.3-kb and 0.9-kb isoforms, induces tyrosine phosphorylation of Tie-2 in human umbilical vein endothelial cells. These data suggest that isoforms 1.3 kb and 0.9 kb could serve as dominant negative molecules for the full-length Ang-1. The possible involvement of the newly identified Ang-1 isoforms in angiogenesis and in growth and differentiation of hematopoietic progenitor cells provides a greater complexity to these processes.

Thrombin, a multifunctional protein, has been found to be involved in cellular mitogenesis, tumor growth, and metastasis, in addition to its well known effects on the initiation of platelet aggregation and secretion and the conversion of fibrinogen to fibrin to form blood clots. These properties of thrombin rely on its action as a serine protease, which cleaves the N-terminal region of a 7-transmembrane G protein receptor (protease-activated receptor, PAR-1), thus exposing a tethered end hexapeptide sequence capable of activating its receptor. Little is known about its effect on genes that regulate the cell cycle. This study was undertaken to investigate the possible mechanisms by which thrombin regulates tumor cell growth in several tumor cell lines: human CHRF megakaryocyte, DU145 prostate, MDAMB231 and MCF7 breast, U3A fibrosarcoma, and 2 murine fibroblast cell lines, MEFp53(-/-) and CD STAT(-/-). We have found that thrombin under the conditions of culture employed inhibits cell growth by both up-regulation of p21(waf/cip1) and induction of caspases via its PAR-1 receptor. The increased expression of p21(waf/cip1) by thrombin was p53 independent, STAT1 dependent, and protein synthesis independent. This was associated with tyrosine phosphorylation of JAK2 and STAT1, and nuclear translocation of STAT1. Induction of apoptosis is also PAR-1-specific, STAT1-dependent, and associated with up-regulation of caspases 1, 2, and 3. Our study establishes, for the first time, a link between PAR-1 receptor activation with the STAT signal pathway, which leads to cell cycle control and apoptosis. This observation broadens our understanding of the mechanism of PAR-1 activation and its effect on cell growth, and could possibly lead to therapeutic approaches for the treatment of cancer.

Thrombin-treated tumor cells induce a metastatic phenotype in experimental pulmonary murine metastasis. Thrombin binds to a unique protease-activated receptor (PAR-1) that requires N-terminal proteolytic cleavage for activation by its tethered end. A 14-mer thrombin receptor activation peptide (TRAP) of the tethered end induces the same cellular changes as thrombin. Four murine tumor cells (Lewis lung, CT26 colon CA, B16F10 melanoma, and CCL163 fibroblasts) contain PAR-1, as detected by reverse transcriptase-polymerase chain reaction (RT-PCR). B16F10 cells did not contain the two other thrombin receptors, PAR-3 and glycoprotein Ib. TRAP-treated B16F10 tumor cells enhance pulmonary metastasis 41- to 48-fold (n = 17). Thrombin-treated B16F10 cells transfected with full-length murine PAR-1 sense cDNA (S6, S7, S14, and S22) enhanced their adhesion to fibronectin 1.5- to 2.4-fold (n = 5, P < .04), whereas thrombin-treated wild-type cells do not. S6 (adhesion index, 1.5-fold) and S14 (index, 2.4-fold) when examined by RT-PCR and Northern analysis showed minimal expression of PAR-1 for S6 over wild-type and considerable expression for S14. Immunohistochemistry showed greater expression of PAR-1 for S14 compared with wild-type or empty-plasmid transfected cells. In vivo experiments with the thrombin-treated S14 transfectant showed a fivefold to sixfold increase in metastases compared with empty-plasmid transfected thrombin-treated naive cells or S6 cells (n = 20, P = .0001 to .02). Antisense had no effect on thrombin-stimulated tumor mass. Thus, PAR-1 ligation and expression enhances and regulates tumor metastasis.

We hypothesized that nitric oxide (NO) production by the fetal ductus arteriosus is limited because of low fetal PO2, but that at neonatal PO2, NO might be an important regulator of ductus arteriosus tone. We exposed isolated rings of fetal lamb ductus arteriosus to elevated PO2. L-NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), and methylene blue and 6-anilino-5,8-quinolinedione (LY83583), inhibitors of guanylate cyclase, produced constriction of the ductus arteriosus. When ductus arteriosus rings were exposed to low PO2, L-NAME had no effect, and methylene blue and LY83583 had only a small effect on ductus arteriosus tone. Sodium nitroprusside and calcium ionophore A23187 relaxed ductus arteriosus rings more than aortic rings, and relaxed ductus arteriosus rings from immature fetuses more than those from late gestation fetuses. In contrast, ductus arteriosus rings from both early and late gestation were equally sensitive to 8-bromo-cGMP. By both reverse transcriptase-polymerase chain reaction and immunohistochemistry, endothelial cell NOS and inducible calcium-independent NOS, but not nerve cell NOS, were detected in the ductus arteriosus. Inducible NOS was expressed only by endothelial cells lining the ductus arteriosus lumen; in contrast, endothelial cell NOS was expressed by both luminal and vasa vasorum endothelial cells. The role of inducible NOS in the ductus arteriosus is uncertain because the potency of a specific inducible NOS inhibitor in constricting the ductus arteriosus was negligible compared with that of an endothelial cell NOS inhibitor. We speculate that NO may be an important regulator of ductus arteriosus tone at high but not low PO2. The endothelial cell NOS isoform found in vasa vasorum may be an important source of NO because removal of ductus arteriosus luminal endothelium only partially blocks the effects of L-NAME, methylene blue, and LY83583.

Hypoxia-inducible factor-1alpha (HIF-1 alpha) has been reported to have an important role in the metabolism and synthesis of extracellular matrix of the nucleus pulposus cells (NPCs) and was assumed to be involved in the process of intervertebral disc degeneration. The objective of this study was to investigate the role of HIF-1alpha in disc degeneration in vivo using a conditional HIF-1alpha knockout (KO) mouse model. ShhCre transgenic mice were mated with HIF-1 alpha fl/fl mice to generate conditional HIF-1alpha KO mice (HIF-1alpha fl/fl-ShhCre+). Three mice of each genotype (Wide-type and HIF-1alpha KO) at the age of 3 days, 6, and 12 weeks were sacrificed after genotyping. Five lumbar disc samples were harvested from each mouse, with a total of 45 disc samples for each genotype. In situ hybridization and immunohistochemical analysis were used to check the efficacy of HIF-1alpha knockout. Histological grading of the disc degeneration was performed according to the classification system proposed by Boos et al. Picro-sirius red staining, Safranine O/fast green staining and immunohistochemical study were used to evaluate the expression of aggrecan, type-II collagen and vascular endothelial growth factor (VEGF). Histologic analysis revealed more NPC deaths and signs of degeneration in HIF-1alpha KO mice and the degeneration scores of HIF-1alpha KO mice were significantly higher than those of the Wide-type mice at the age of 6 weeks and 12 weeks. There were less expressions of aggrecan, type-II collagen and VEGF in the intervertebral discs of HIF1-alpha KO mice than in those of wild-type mice. Taken together, the results of our study indicated that HIF-1alpha is a pivotal contributor to NPC survival and the homeotasis of extracellular matrix through the HIF-1alpha/VEGF signaling pathway, and plays an important role in the development of disc degeneration.

Wu-tou decoction (WTD), a traditional Chinese medicine (TCM) formula, is composed of Aconiti Radix Cocta, Ephedrae Herba, Paeoniae Radix Alba, Astragali Radix and Glycyrrhiza Radix Preparata, and it has been used for more than a thousand years to treat rheumatic arthritis, rheumatoid arthritis and pain of joints, while the active constitutions of WTD are unclear. In this research, an ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) method in both positive and negative ion mode was established to investigate the major constitutions in WTD. A Waters ACQUITY UPLC BEH C18 column was used to separate the aqueous extract of WTD. Acetonitrile and 0.1% aqueous formic acid (v/v) were used as the mobile phase. 74 components including alkaloids, monoterpene glycosides, triterpene saponins, flavones and flavone glycosides were identified or tentatively characterized in WTD based on the accurate mass within 15 ppm error and tandem MS behavior. All the constitutions were also detected in the corresponding individual herbs. These results will provide a basis for further study in vivo of WTD and the information of potential new drug structure for treating rheumatic arthritis and rheumatoid arthritis.

Squamous cell carcinoma of the oral cavity spreads by initial invasion of the laminin-rich basement membrane. We examined the adhesion and motility of human oral SCC cells and normal mucosal keratinocytes and found that the SCC cells readily attached and migrated on laminin 1 substrates but migrated poorly on collagen type I and fibronectin. The normal keratinocytes, however, adhered poorly to and were non-motile on laminin 1 yet readily and preferentially attached and migrated on fibronectin and collagen type I. Analysis with blocking anti-integrin antibodies showed that the SCC cells used the alpha 6 beta 1 complex to attach and migrate on laminin 1 and that this activity was confined to the E8 long arm fragment of laminin. Affinity chromatography on laminin-Sepharose columns revealed that the SCC cells, but not normal keratinocytes, expressed high levels of the alpha 6 beta 1 laminin 1 receptor. Metabolic pulse-chase analysis indicated that in contrast to the SCC cells, keratinocytes did not have a stable pool of beta 1 subunit precursor. Preferential pairing of alpha 6 with beta 4 and the deficiency in pre-beta 1 levels appear to account for the failure of keratinocytes to form significant alpha 6 beta 1 complex. Additionally, the presence of laminin 1 in co-coating experiments blocked keratinocyte adhesion to other immobilized ligands, such as collagen type I or fibronectin. This anti-adhesive effect seemed to reflect a general paralysis of cell adhesive function, since laminin 1 also diminished the adhesion of keratinocytes to substrates coated with immobilized anti-integrin subunit antibody. The inhibitory activity of laminin 1 resided in the E1' and E8 fragments, and not in the E3, E4 or G domains. Collectively, our results indicate that laminin 1 is a restrictive ligand for normal keratinocytes, apparently because of their failure to assemble and express the alpha 6 beta 1 complex or other functional laminin receptors and their sensitivity to the anti-adhesive activity of laminin itself. The elevated expression of alpha 6 beta 1 following malignant conversion of muscosal keratinocytes promotes their migration on laminin, a process important during invasion and metastasis.