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During the simulation of global multi-resolution terrain environment, we need to build a multi-resolution terrain data cache pool and use a certain indexing mechanism. Based on the scheme of global data delamination and division by terrain data pyramid model structure, this paper presented a hash indexing algorithm adapted to terrain data block cache, and discussed the keyword design method and the collision solution method. Finally, some experiments on the key questions of hash technique including collision ratio and time cost are carried out.

Stepped frequency signal is an important high distance resolution signal, this property is realized by combining several pulse signal, so it is easy to be effected by targets radial motion. Here we analyzed how targets radial motion affects the synthesis HRRP, then a method of velocity measurement is provided, then compensation using the predicted velocity.

Mn doped graphene-based dilute magnetic semiconductors (DMS) are investigated using the first-principle calculation based on density functional theory. In this paper, the Mn-C bond length, formation energy and magnetic moment are calculated in different doping systems and their density of states is made a detailed analysis. It is found that Mn-doped graphene has strong ferromagnetic properties and the magnetic moments of graphene supercells are different with the impurity concentrations. These supercells of a Mn atom substituting a C atom are increasingly stable with extending cells and the 11×11 supercell possesses the biggest magnetic moment of 3.8μB in these systems. The analysis of the density of states indicates the magnetic properties of Mn-doped graphene derive from the p-d exchange mechanism.

Magnetic properties of 6H-SiC doped with transition metal (TM) atoms are calculated using the density functional theory method (DFT). It is shown that TM doped in a 6H-SiC host may have both magnetic and nonmagnetic states. From the figures of their density of states (DOS) and partial density of states (PDOS) and to compare the energy differences between ferromagnetic and nonmagnetic states, we demonstrate that Cr and Mn-doped 6H-SiC emerge a half-metallic ferromagnetic state, Co and Ni-doped 6H-SiC create very little magnetic features, while Fe-doped 6H-SiC is in the nonmagnetic state. We also calculate the energy differences between ferromagnetic and antiferromagnetic of Cr, Mn and Fe-doped 6H-SiC in the doping concentration (8.34%). It is found that the energy of the antiferromagnetic state is lower than that of the ferromagnetic state.

The molecular mechanisms for the retrograde motor dynein-dynactin to unload its cargoes at their final destination remain to be elucidated. In this study, we have investigated the regulatory mechanism underlying release of retromer-associated cargoes at the trans-Golgi network (TGN). We report that phosphotidylinositol-4-phosphate (PtdIns(4)P), a Golgi-enriched phosphoinositide, negatively regulates the protein-protein interaction between the p150(Glued) subunit of dynein-dynactin and the retromer component SNX6. We show that PtdIns(4)P specifically facilitates dissociation of retromer-mediated membranous cargoes from the motor at the TGN and uncover an important function for PtdIns(4)P in the spatial control of retrograde vesicular trafficking to the TGN membrane. PtdIns(4)P also regulates SNX4-mediated retrograde vesicular trafficking to the endocytic recycling compartment by modulating its interaction with dynein. These results establish organelle-specific phosphoinositide regulation of motor-cargo interaction as a mechanism for cargo release by molecular motors at target membrane.

In this paper, an AlN-based hot-film wind speed and direction sensor was designed through the thermal analysis of two-dimensional flow field, realized the measurement of wind speed and direction. The 2D micro structure sensor was prepared by lithography process and laser micro machining process on 0.2mm thick AlN substrate. It is composed of a heater in the middle, four temperature detectors around and a temperature sensor. The sensor has a small volume, a low power consumption, it is easily to be integrated, can be applied to a variety of portable flow meters and gas flow detectors of the complex environment.

Ti3Al intermetallic alloy is a hard formed material with many advantages for aviation and aerospace applications. Superplastic forming (SPF) is an ideal process for Ti3Al alloy to form sheet metal component. The thickness distribution of U cross-section circular parts, which were superplastically formed in two different female die cavity, were predicted by FEM software. According to female die forming thickness distribution, preforming die cavity was designed and was optimized by FEM software. Superplastic bugling tests with and without preforming were carried out. The thickness of parts were measured and compared with predictions by FEM software. The results showed that preforming can promote thickness uniformity efficiently in female die forming. In this experiment, the thickness difference range of the part formed with preforming reduced 75.8% compared with part formed without preforming.

Owing to the intrinsic factors and some extrinsic environmental conditions, many foods, agricultural products and Chinese materia medicas (CMMs), if not handled properly in the processes of growth, harvesting, processing and storage, can be easily contaminated by all kinds of molds to produce mycotoxins of serious toxicity, which will not only affect the quality, safety and effectiveness of CMMs, but also result in potential threatens to human and animal's health and life. Therefore, in recent decades, it has become the focus on how to prevent and control the foods, agricultural products and CMMs from being moldy and producing toxicity for scientific preservation. Many Chinese herbal medicines (CHMs) especially those with high content of volatile oils with strong antifungal activities have been applied for the scientific preservation of foods, agricultural products and CMMs. Based on these situations, natural anti-mildew agents have been further developed and made into some useful dosage forms, such as tablets, aerosol, liposomes and inclusion, which will not only greatly expand the application scope of CHMs to make the use of anti-mildew agents more convenient, but also achieve the sustained or controlled release of the antifungal effect for scientific preservation of foods, agricultural products and CMMs.

Elevated IL-6 has been implicated in depression. The anti-inflammatory effects of exercise may be associated with its clinical efficacy for depression. We determined if serum IL-6 levels were altered by 12 weeks of physical exercise, and if IL-6 levels were associated with baseline depression severity and change in depression severity in response to exercise. Data from 116 adults (42.7±11.5y) with mild-to-moderate depression (Patient Health Questionnaire >9) who participated in the physical exercise arm of the Regassa RCT (www.regassa.se) were analyzed. Participants were requested to complete three 60-min exercise sessions weekly for 12 weeks. Blood samples were provided at baseline and post-intervention following an overnight fast and were analyzed for serum levels of IL-6 using ELISA. IL-6 values were logarithm-transformed. Higher baseline serum IL-6 levels were significantly associated with reduced depression severity after exercise. Reduced IL-6 levels following exercise were significantly associated with parallel reductions in depression severity. These findings are consistent with a previously reported association between reduced serum IL-1β levels and reduced depression severity following 12 weeks of physical exercise in 105 depressed adults. Findings support associations between IL-6, depressive symptoms, and exercise response, and provide support for the plausible involvement of IL-6 in the antidepressive effect of exercise.

Scathophaga stercoraria (Linnaeus, 1758) is a well-established insect model species involved in numerous investigations on behavior, biology, phylogeny, genetics and evolution. The antennal sensilla of S. stercoraria are examined via scanning electron microscopy in order to emphasize their importance on taxonomy and phylogeny. On antennal scape and pedicel, both microtrichiae and several sharp-tipped mechanoreceptors are observed, while another two structures, setiferous plaques and pedicellar button, are also detected on antennal pedicel. One type of sensory pit and four types of antennal sensilla, including trichoid sensilla, basiconic sensilla, coeloconic sensilla and clavate sensilla, are observed on antennal funiculus. Similarity and disparity of setiferous plaques among different calyptrate groups are analyzed in terms of phylogeny. The phylogenetic results supported by morphology of setiferous plaques strongly accord with the cladistic relations based on known molecular tree, implying the potential taxonomic and phylogenetic implications of the plaques in Calyptratae.

Co-doped ceria of Ce0.8Gd0.2−x Ca x O2-δ (x = 0−0.2), were prepared by oxalate co-precipitation method. Their structures and conductivities were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and AC impedance spectroscopy (IS). All the electrolytes were found to be single phase with cubic fluorite structure. SEM cross-section image showed relatively uniform grains with distinct and clean grain boundaries. The chemical states of the surface of the prepared samples were analyzed by XPS. Though Gd and Ca were present in their characteristic chemical state, Ce was found in single Ce4+ state or in mixed Ce4+ and Ce3+ states. IS measurements indicated that the conductivities for Ce0.8Gd0.2–x Ca x O2-δ pellets increased with increasing the sintering temperature. Moreover, co-doping with appropriate ratio of gadolinium and calcium was found to effectively enhance the conductivity in comparison to the singly doped ceria. The isothermal conductivity plots showed that sample Ce0.8Gd0.1Ca0.1O2-δ had the maximum conductivity with minimum activation energy (σ 700°C = 0.0742 S/cm, Ea = 0.58 eV), which is much higher compared to the conductivity exhibited by most of the reported codoped ceria compositions.

Objective: Identification of the primary tumour can prolong the life expectancy of patients with primary unknown cervical lymph node metastasis (PUCLNM) through targeted therapy. This study investigated the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET-CT) at identifying primaries in patients with PUCLNM. Methods: Twenty-seven patients (21 males and 6 females, median age 48.2 ± 16.3, age range 30–73) with PUCLNM underwent FDG PET-CT to search for the primary tumour, which could not be detected by conventional diagnostic modalities. The results were analysed and correlated with either pathological findings or clinical follow up. Results: Pathological FDG uptake suspicious for the primary was detected in 13 cases, while the primary tumour remained occult in 14 cases. Eleven of 13 patients with suspected primaries were confirmed by histological findings. One with a coexisting second tumour and three with unexpected distant metastases were found in patients with confirmed primaries. The most common primary location in patients with PUCLNM found in our study was nasopharynx. In those 14 patients with negative FDG PET-CT results, only one patient had a primary malignancy that was proven histologically after endoscopy with biopsy during a period of clinical follow up. The sensitivity, specificity, accuracy and positive predictive values of FDG PET-CT were 91.7, 86.7, 88.9 and 84.6%, respectively. Conclusion: FDG PET-CT is a useful tool to help search for unknown primaries in patients with cervical lymph node metastasis and has an acceptable diagnostic yield for the detection of distant malignancies.

A series of novel N-phenylsulfonylnicotinamide derivatives (1–24) have been synthesized and evaluated as potential EGFR tyrosine kinase (TK) inhibitors. Among all the compounds, compound 10 (5-bromo-N-(4-chlorophenylsulfonyl)nicotinamide) showed the most potent growth inhibitory activity against EGFR TK and antiproliferative activity of MCF-7 cancer cell line in vitro, with IC50 value of 0.09 and 0.07 μM. Docking simulation was performed to insert compound 10 into the EGFR TK active site to determine the probable binding model. Based on the preliminary results, compound 10 with potent inhibitory activity to tumor growth may be a potential anticancer agent.

Aims and Background Despite progress in treatment techniques, the five-year survival rate of nasopharyngeal carcinoma (NPC) is disappointing. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) can selectively induce apoptosis in most tumor cells while sparing normal cells. Given the antiapoptotic functions of Bcl-2 and Akt, we examined the effects of targeting these pathways alone or simultaneously on TRAIL apoptosis in NPC cell lines. Methods and Study Design We first tested the cytotoxic effect of TRAIL and the expression of death receptors, Bcl-2, Akt, and p-Akt on four NPC cell lines by MTT and Western blotting, respectively. Small interfering RNAs (siRNAs) targeting Bcl-2 and PI3–K inhibitor (LY294002) were used alone or combined with TRAIL in the cell lines and cytotoxicity was examined by MTT. Apoptosis rates, mitochondrial transmembrane potential, and apoptotic pathway signals were detected by flow cytometric analysis, DiOC6(3) assays, and Western blotting after the various combination treatments on CNE-2, the cell line that was most resistant to TRAIL. Results Although no direct correlation between the sensitivity to TRAIL and the relative expression levels of Bcl-2 and activated Akt was found in the NPC cell lines examined, siRNA mediated the downregulation of Bcl-2 and LY294002-induced inactivation of Akt, increasing the sensitivity of all examined NPC cell lines to TRAIL. Synergistic enhancement of TRAIL-mediated cytotoxicity was observed in combination treatment of Bcl-2 siRNA and LY294002 compared to cells treated with each treatment alone. The synergistic effects were mediated through increased apoptotic signaling of the mitochondrial pathway, as was evident from the more increased mitochondrial depolarization, activation of caspase-9 and caspase-3, and suppression of XIAP. Conclusions This study provides proof of principle that TRAIL combined with simultaneously targeting the Bcl-2 and Akt signaling pathways may have potential as a novel future treatment strategy for NPC.

A series of Ce{sub 0.8}Gd{sub 0.2-x}Nd{sub x}O{sub 2-{delta}} (x = 0-0.20) compositions have been synthesized by citric acid-nitrate combustion method. XRD measurements indicate that all the obtained materials crystallized in cubic fluorite-type structure. Lattice parameters were calculated by Rietveld method and the parameter a values in Ce{sub 0.8}Gd{sub 0.2-x}Nd{sub x}O{sub 2-{delta}} system obey Vegard's law, a (A) = 5.4224 + 0.1208x. The obtained powders have good sinterability and the relative density could reach above 95% after being sintered at 1400 {sup o}C. Impedance spectroscopy measurements indicated that the conductivity of Ce{sub 0.8}Gd{sub 0.2-x}Nd{sub x}O{sub 2-{delta}} first increased and then decreased with Nd dopant content x. The maximum conductivity, {sigma}{sub 700{sup o}C} = 6.26 x 10{sup -2} S/cm, was found in Ce{sub 0.8}Gd{sub 0.12}Nd{sub 0.08}O{sub 1.9} when sintered at 1300 {sup o}C. The corresponding activation energies of conduction had a minimum value E{sub a} = 0.676 eV. The results tested experimentally the validity of the effective atomic number concept of recent density functional theory, which had suggested that co-dopant with effective atomic number between 61 (Pm) and 62 (Sm) was the ideal dopant exhibiting high ionic conductivity and low activation energy.

Both retrolinkin and its interaction partner endophilin A1 are required for BDNF-induced dendrite outgrowth of cultured hippocampal neurons. They function sequentially in an early endocytic trafficking pathway for BDNF-activated TrkB, which provides spatiotemporal control of downstream ERK signaling from endosomes., Brain-derived neurotrophic factor (BDNF) binds to its cell surface receptor TrkB to regulate differentiation, development, synaptic plasticity, and functional maintenance of neuronal cells. Binding of BDNF triggers TrkB dimerization and autophosphorylation, which provides docking sites for adaptor proteins to recruit and activate downstream signaling molecules. The molecular mechanisms underlying BDNF–TrkB endocytic trafficking crucial for spatiotemporal control of signaling pathways remain to be elucidated. Here we show that retrolinkin, a transmembrane protein, interacts with endophilin A1 and mediates BDNF-activated TrkB (pTrk) trafficking and signaling in CNS neurons. We find that activated TrkB colocalizes and interacts with the early endosome marker APPL1. Both retrolinkin and endophilin A1 are required for BDNF-induced dendrite development and acute extracellular signal-regulated kinase activation from early endosomes. Suppression of retrolinkin expression not only blocks BDNF-triggered TrkB internalization, but also prevents recruitment of endophilin A1 to pTrk vesicles trafficking through APPL1-positive endosomes. These findings reveal a novel mechanism for BDNF–TrkB to regulate signaling both in time and space through a specific membrane trafficking pathway.

A novel method has been developed for the rapid separation and determination of 24 Sulfonamides (SAs) in bovine milk by using ultra-performance liquid chromatography tandem quadrupole mass spectrometry (UPLC-MS/MS) in ten minutes. Sulfonamides residues from bovine milk were treated with acetonitrile, followed by homogenizing, ultrasound treating, and centrifuging. The aforementioned procedure is repeated one additional time. A part of the extracts was taken to dryness and defatted twice. The analysis was performed on an Acquity UPLCTM BEH C18 column under the mobile phase which is composed of 0.2% acetic acid in water and acetonitrile. The analytes were detected by multiple reaction monitoring (MRM) in the positive ion scan mode. The calibration curves showed acceptable linearity in the concentration range from 0.2 to 100 ng mL−1 with correlation coefficients (r2) above 0.992. The mean recoveries of 24 SAs in different standard-spiked levels were in the range of 60.59–116.66%; RSD% was 2.92%∼18.64%. Resul...

A novel method based on the molecularly imprinted solid-phase extraction (MISPE) procedure has been developed for the simultaneous determination of concentrations of sulfonylurea herbicides such as chlorsulfuron (CS), monosulfuron (MNS), and thifensulfuron methyl (TFM) in maize samples by liquid chromatography–tandem quadrupole mass spectrometry (LC–MS/MS). The molecularly imprinted polymer (MIP) for sulfonylurea herbicides was synthesized by precipitation polymerization using chlorsulfuron as the template molecule, 2-(diethylamino)ethyl methacrylate (DEAMA) as the functional monomer, and trimethylolpropane trimethacrylate (TRIM) as the cross-linker. The selectivities of the chlorsulfuron template and its analogs on the molecularly imprinted polymer were evaluated by high-performance liquid chromatography (HPLC). The extraction and purification procedures for the solid-phase extraction (SPE) cartridge with a molecularly imprinted polymer as the adsorbent for the selected sulfonylurea herbicides were then established. A molecularly imprinted solid-phase extraction method followed by high-performance liquid chromatography–tandem mass spectrometry for the determination of chlorsulfuron, monosulfuron, and thifensulfuron methyl was also established. The mean recoveries of these compounds in maize were in the range 75–110% and the limits of detection (LOD) of chlorsulfuron, monosulfuron, and thifensulfuron methyl were 0.02, 0.75, and 1.45 μg kg−1, respectively. It was demonstrated that the MISPE–HPLC–MS/MS method could be applied to the determination of chlorsulfuron, monosulfuron, and thifensulfuron methyl in maize samples.

Antennal sensory units in nymphs and adults of the spotted Lanternfly, Lycorma delicatula (White) (Hemiptera: Fulgoromorpha: Fulgoridae), an economically important plant pest, are studied with scanning electron microscopy. Sensilla trichodea / chaetica type recognition is based on their external morphology and ratio of their size to diameter. The flagellum Bourgoin's organ is a complex sensory unit with 2-3 internal sensilla coeloconica. During nymphal stages, the sensory surface available for a chemoreceptive function particularly increases with the number and size of sensilla placodea on the antennal pedicel. From first to fourth instar and to adult males and females, plate organ sensory surface is estimated to increase respectively by 33x, 68x and 125x (= 2.72 mm2 and 5.02 mm2 respectively for males and females). The most important increase (5x) occurs between second and third instar. In parallel, a distinctive pair of plate organs on the flagellum decreases in size from first to third instar, and disappears. Sexual dimorphism occurs in sensilla placodea in adults. Diversity, disparity and evolution of nymphal sensilla, and their sexual dimorphism in adults are discussed in the context of the species and planthopper behaviour.

The retromer is a protein complex that mediates retrograde transport of transmembrane cargoes from endosomes to the trans-Golgi network (TGN). It is comprised of a cargo-selection subcomplex of Vps26, Vps29 and Vps35 and a membrane-binding coat subcomplex of sorting nexins (SNXs). Previous studies identified SNX1/2 as one of the components of the SNX subcomplex, and SNX5/6 as candidates for the second SNX. How the retromer-associated cargoes are recognized and transported by molecular motors are largely unknown. In this study, we found that one of SNX1/2's dimerization partners, SNX6, interacts with the p150(Glued) subunit of the dynein/dynactin motor complex. We present evidence that SNX6 is a component of the retromer, and that recruitment of the motor complex to the membrane-associated retromer requires the SNX6-p150(Glued) interaction. Disruption of the SNX6-p150(Glued) interaction causes failure in formation and detachment of the tubulovesicular sorting structures from endosomes and results in block of CI-MPR retrieval from endosomes to the TGN. These observations indicate that in addition to SNX1/2, SNX6 in association with the dynein/dynactin complex drives the formation and movement of tubular retrograde intermediates.

Appropriate clearance of apoptotic cells (cell corpses) is an important step of programmed cell death. Although genetic and biochemical studies have identified several genes that regulate the engulfment of cell corpses, how these are degraded after being internalized in engulfing cell remains elusive. Here, we show that VPS-18, the Caenorhabditis elegans homologue of yeast Vps18p, is critical to cell corpse degradation. VPS-18 is expressed and functions in engulfing cells. Deletion of vps-18 leads to significant accumulation of cell corpses that are not degraded properly. Furthermore, vps-18 mutation causes strong defects in the biogenesis of endosomes and lysosomes, thus affecting endosomal/lysosomal protein degradation. Importantly, we demonstrate that phagosomes containing internalized cell corpses are unable to fuse with lysosomes in vps-18 mutants. Our findings thus provide direct evidence for the important role of endosomal/lysosomal degradation in proper clearance of apoptotic cells during programmed cell death.

Retromer is an evolutionarily conserved multimeric protein complex that mediates intracellular transport of various vesicular cargoes and functions in a wide variety of cellular processes including polarized trafficking, developmental signaling and lysosome biogenesis. Through its interaction with the Rab GTPases and their effectors, membrane lipids, molecular motors, the endocytic machinery and actin nucleation promoting factors, retromer regulates sorting and trafficking of transmembrane proteins from endosomes to the trans-Golgi network (TGN) and the plasma membrane. In this review, I highlight recent progress in the understanding of retromer-mediated protein sorting and vesicle trafficking and discuss how retromer contributes to a diverse set of developmental, physiological and pathological processes.

Background Telomeres are protective DNA–protein complexes forming the chromosome ends. TL differs between tissues. Shorter telomere length (TL) in blood leukocytes (LTL) has been associated with major depression, and with previous exposure to childhood adversity. TL studies on non-invasively sampled salivary DNA are less common. Telomerase, with its catalytic subunit hTERT, counteracts telomere shortening. Reduced telomerase activity associates with depression-like behavior in mice. Recently, the minor allele of the hTERT polymorphism rs2736100 was associated with shorter LTL among primarily healthy individuals. We hypothesized that (i) TL in saliva DNA is shortened in adults with a history of depression, and that (ii) rs2736100 is implicated in depression and depressive episodes in bipolar disorder type 1 (BD1). Methods Individuals with a history of depression and those without (controls) were identified using self-reported questionnaires from a well-characterized population-based cohort. Clinical BD1 patients were diagnosed by specialized psychiatrists. Saliva TL was measured in age-matched depressed individuals and controls (n=662) using qRT-PCR. rs2736100 was genotyped in 436 depressed individuals, 1590 controls, and 368 BD1 patients. Results Saliva TL was shorter in depressed individuals compared to controls. The rs2736100 minor allele was associated with depression among those without experience of childhood adversity, and with number of depressive episodes in BD1 patients responding well to lithium. Limitation Psychopathological symptoms were recorded at two time points only, 3 and 6 years prior to DNA sampling. Conclusions This is the first report on hTERT genetic variation in mood disorder. It proposes that genetic variation in hTERT may influence the susceptibility to depression.

Dendritic spines are actin-rich membrane protrusions that are the major sites of excitatory synaptic input in the mammalian brain, and their morphological plasticity provides structural basis for learning and memory. Here we report that endophilin A1, with a well-established role in clathrin-mediated synaptic vesicle endocytosis at the presynaptic terminal, also localizes to dendritic spines and is required for spine morphogenesis, synapse formation and synaptic function. We identify p140Cap, a regulator of cytoskeleton reorganization, as a downstream effector of endophilin A1 and demonstrate that disruption of their interaction impairs spine formation and maturation. Moreover, we demonstrate that knockdown of endophilin A1 or p140Cap impairs spine stabilization and synaptic function. We further show that endophilin A1 regulates the distribution of p140Cap and its downstream effector, the F-actin-binding protein cortactin as well as F-actin enrichment in dendritic spines. Together, these results reveal a novel function of postsynaptic endophilin A1 in spine morphogenesis, stabilization and synaptic function through the regulation of p140Cap.

Objective: To investigate the effects of quercetin, an herbal flavonoid, on LPS-induced delay in spontaneous apoptosis, adhesion molecules (CD62L, CD11b/CD18) expression of neutrophils, and superoxide (O 2 − ) generation by LPS-primed fMLP-induced human neutrophils. Methods: Neutrophils were incubated in the presence or absence of lipopolysaccharide (LPS) at a final concentration of 1 μg/ml for 24 hours. Some wells with neutrophils were pre-treated with quecetin at the final concentration ranging from 0–100 μM for 30 min and then 1 μg/ml LPS was added into the cultures for 24 hours. The apoptosis of neutrophils was evaluated by flowcytometry analysis of propidum iodide (PI)-staining of the nuclei and annexin V staning of phosphatidylserine (PS) in the cell membrane. Agarose gel electrophoresis of low molecular weight DNA was performed to analyze DNA fragmentation. The effects of quercetin on adhesion molecules were detected by using flowcytometry analysis. The generation of O 2 − by LPS-primed fMLP-induced neutrophils was determined by reduced cytochrome c assay. Results: LPS markedly inhibited the spontaneous apoptosis of neutrophils, but the inhibitory effect was abrogated after the pre-treatment of neutrophils with quercetin (~40 μM) for 30 min. Quercetin (40 μM) also prevented LPS-induced down-regulation of CD62L expression, up-regulation of CD11b/CD18 expression, and O 2 − generation by fMLP-induced neutrophils. Conclusion: As one of the pro-inflammatory factors, LPS aggravates inflammation through priming neutrophils to synthesize/release cytotoxic contents and prolonging functional lifespan of neutrophils by delaying the spontaneous apoptosis. Thus, our data suggest to us that quercetin might decrease the susceptibility of neutrophils to pro-inflammatory factors (e. g. LPS), which could partially explain the anti-inflammatory mechanisms of quercetin.

Disruption of the BPAG1 (bullous pemphigoid antigen 1) gene results in progressive deterioration in motor function and devastating sensory neurodegeneration in the null mice. We have previously demonstrated that BPAG1n1 and BPAG1n3 play important roles in organizing cytoskeletal networks in vivo. Here, we characterize functions of a novel BPAG1 neuronal isoform, BPAG1n4. Results obtained from yeast two-hybrid screening, blot overlay binding assays, and coimmunoprecipitations demonstrate that BPAG1n4 interacts directly with dynactin p150Glued through its unique ezrin/radixin/moesin domain. Studies using double immunofluorescent microscopy and ultrastructural analysis reveal physiological colocalization of BPAG1n4 with dynactin/dynein. Disruption of the interaction between BPAG1n4 and dynactin results in severe defects in retrograde axonal transport. We conclude that BPAG1n4 plays an essential role in retrograde axonal transport in sensory neurons. These findings might advance our understanding of pathogenesis of axonal degeneration and neuronal death.

Giant axonal neuropathy (GAN), an autosomal recessive disorder caused by mutations in GAN, is characterized cytopathologically by cytoskeletal abnormality. Based on its sequence, gigaxonin contains an NH2-terminal BTB domain followed by six kelch repeats, which are believed to be important for protein–protein interactions (Adams, J., R. Kelso, and L. Cooley. 2000. Trends Cell Biol. 10:17–24.). Here, we report the identification of a neuronal binding partner of gigaxonin. Results obtained from yeast two-hybrid screening, cotransfections, and coimmunoprecipitations demonstrate that gigaxonin binds directly to microtubule-associated protein (MAP)1B light chain (LC; MAP1B-LC), a protein involved in maintaining the integrity of cytoskeletal structures and promoting neuronal stability. Studies using double immunofluorescent microscopy and ultrastructural analysis revealed physiological colocalization of gigaxonin with MAP1B in neurons. Furthermore, in transfected cells the specific interaction of gigaxonin with MAP1B is shown to enhance the microtubule stability required for axonal transport over long distance. At least two different mutations identified in GAN patients (Bomont, P., L. Cavalier, F. Blondeau, C. Ben Hamida, S. Belal, M. Tazir, E. Demir, H. Topaloglu, R. Korinthenberg, B. Tuysuz, et al. 2000. Nat. Genet. 26:370–374.) lead to loss of gigaxonin–MAP1B-LC interaction. The devastating axonal degeneration and neuronal death found in GAN patients point to the importance of gigaxonin for neuronal survival. Our findings may provide important insights into the pathogenesis of neurodegenerative disorders related to cytoskeletal abnormalities.

The endosomal trafficking pathways are essential for many cellular activities. They are also important targets by many intracellular pathogens. Key regulators of the endosomal trafficking include the retromer complex and sorting nexins (SNXs). Chlamydia trachomatis effector protein IncE directly targets the retromer components SNX5 and SNX6 and suppresses retromer-mediated transport, but the exact mechanism has remained unclear. We present the crystal structure of the PX domain of SNX5 in complex with IncE, showing that IncE binds to a highly conserved hydrophobic groove of SNX5. The unique helical hairpin of SNX5/6 is essential for binding, explaining the specificity of SNX5/6 for IncE. The SNX5/6–IncE interaction is required for cellular localization of IncE and its inhibitory function. Mechanistically, IncE inhibits the association of CI-MPR cargo with retromer-containing endosomal subdomains. Our study provides new insights into the regulation of retromer-mediated transport and illustrates the intricate competition between host and pathogens in controlling cellular trafficking.

The formation of functional synapses requires coordinated assembly of presynaptic transmitter release machinery and postsynaptic trafficking of functional receptors and scaffolds. Here, we demonstrate a critical role of presynaptic cadherin/catenin cell adhesion complexes in stabilizing functional synapses and spines in the developing neocortex. Importantly, presynaptic expression of stabilized β-catenin in either layer (L) 4 excitatory neurons or L2/3 pyramidal neurons significantly upregulated excitatory synaptic transmission and dendritic spine density in L2/3 pyramidal neurons, while its sparse postsynaptic expression in L2/3 neurons had no such effects. In addition, presynaptic β-catenin expression enhanced release probability of glutamatergic synapses. Newly identified β-catenin-interacting protein p140Cap is required in the presynaptic locus for mediating these effects. Together, our results demonstrate that cadherin/catenin complexes stabilize functional synapses and spines through anterograde signaling in the neocortex and provide important molecular evidence for a driving role of presynaptic components in spinogenesis in the neocortex.

Hermansky-Pudlak syndrome 6 protein (HPS6) has originally been identified as a subunit of the BLOC-2 protein complex that is involved in the biogenesis of lysosome-related organelles. Here, we demonstrate that HPS6 directly interacts with the dynactin p150 Glued subunit of the dynein–dynactin motor complex and acts as cargo adaptor for the retrograde motor to mediate the transport of lysosomes from the cell periphery to the perinuclear region. Small interfering RNA (siRNA)-mediated knockdown of HPS6 in HeLa cells not only partially blocks centripetal movement of lysosomes but also causes delay in lysosome-mediated protein degradation. Moreover, lysosomal acidification and degradative capacity, as well as fusion between late endosomes and/or multivesicular bodies and lysosomes are also impaired when HPS6 is depleted, suggesting that perinuclear positioning mediated by the dynein–dynactin motor complex is required for lysosome maturation and activity. Our results have uncovered a so-far-unknown specific role for HPS6 in the spatial distribution of the lysosomal compartment.

The practicability of the IPOS (input-parallel and output-series) DC-DC converters with equal pulse width of driving signals for all the switching devices is studied in this paper. Push–pull forward converters, double-transistor forward converters, and phase-shifted full-bridge converters are chosen as the modular cells in the IPOS system. The influence of the circuit component parameters for the output voltage of each module is analyzed. The research conclusions show that the IPOS dc-dc converters can be controlled with equal pulse width of driving signals in some low cost area.

The yeast [PSI+] element represents a new type of genetic inheritance, in which changes in phenotype are transmitted by a 'protein only' mechanism reminiscent of the 'protein-only' transmission of mammalian prion diseases. The underlying molecular mechanisms for both are poorly understood and it is not clear how similar they might be. Sup35, the [PSI+] protein determinant, and PrP, the mammalian prion determinant, have different functions, different cellular locations and no sequence similarity; however, each contains five imperfect oligopeptide repeats-PQGGYQQYN in Sup35 and PHGGGWGQ in PrP. Repeat expansions in PrP produce spontaneous prion diseases. Here we show that replacing the wild-type SUP35 gene with a repeat-expansion mutation induces new [PSI+] elements, the first mutation of its type among these newly described elements of inheritance. In vitro, fully denatured repeat-expansion peptides can adopt conformations rich in beta-sheets and form higher-order structures much more rapidly than wild-type peptides. Our results provide insight into the nature of the conformational changes underlying protein-based mechanisms of inheritance and suggest a link between this process and those producing neurodegenerative prion diseases in mammals.

The [PSI+] factor of S. cerevisiae represents a new form of inheritance: cytosolic transmission of an altered phenotype is apparently based upon inheritance of an altered protein structure rather than an altered nucleic acid. The molecular basis of its propagation is unknown. We report that purified Sup35 and subdomains that induce [PSI+] elements in vivo form highly ordered fibers in vitro. Fibers bind Congo red and are rich in β sheet, characteristics of amyloids found in certain human diseases, including the prion diseases. Some fibers have distinct structures and these, once initiated, are self-perpetuating. Preformed fibers greatly accelerate fiber formation by unpolymerized protein. These data support a “protein-only” seeded polymerization model for the inheritance of [PSI+].

Dexamethasone (Dex) has anti-inflammatory and immunomodulatory properties against many conditions. There is a potential teratogenic risk, however, for pregnant women receiving Dex treatment. It has been claimed that Dex exposure during pregnancy could affect osteogenesis in the developing embryo, which still remains highly controversial. In this study, we employed chick embryos to investigate the effects of Dex exposure on skeletal development using combined in vivo and in vitro approach. First, we demonstrated that Dex (10(-8)-10(-6)μmol/egg) exposure resulted in a shortening of the developing long bones of chick embryos, and it accelerated the deposition of calcium salts. Secondly, histological analysis of chick embryo phalanxes exhibited Dex exposure inhibited the proliferation of chondrocytes, increased apoptosis of chondrocytes and osteocytes, and led to atypical arranged hypertrophic chondrocytes. The expression of genes related to skeletogenesis was also analyzed by semi-quantitative RT-PCR. The expression of ALP, Col1a2 and Col2a1 was decreased in the Dex treated phalanxes. A detectable increase was observed in Runx-2 and Mmp-13 expression. We next examined how Dex affected the different stages of skeletogenesis in vitro. Utilizing limb bud mesenchyme micromass cultures, we determined that Dex exposure exerted no effect on apoptosis but impaired chondrogenic cell proliferation. Interestingly, low dose of Dex moderately prompted nodule formation as revealed by alcian blue staining, but higher doses of Dex significantly inhibited similar chondrogenic differentiation. Dex exposure did not induce apoptosis when the chondrogenic precursors were still at the mesenchymal stage, however, cell viability was suppressed when the mesenchyme differentiated into chondrocytes. Alizarin red staining revealed that the capacity to form mineralized bone nodules was correspondingly enhanced as Dex concentrations increased. The mRNA level of Sox-9 was slightly increased in mesenchymal cell mass treated by low concentration of Dex. Mmp-13 expression was obviously up-regulated by Dex in both mesenchymal cells and primary chondrocyte cultures. And Col10a1 expression was also increased by Dex exposure in chondrocyte. In summary, we have revealed that different concentrations of Dex exposure during early gestation could exert a biphasic effect on vertebrate skeletal development.

A series of novel schiff base derivatives (H(1)-H(20)) containing pyrazine and triazole moiety have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of β-ketoacyl-acyl carrier protein synthase III (FabH). These compounds were assayed for antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis and Bacillus amyloliquefaciens and selected compounds among them were tested for their Escherichia coli FabH inhibitory activity. Based on the biological data, compound H(17) showed the most potent antibacterial activity with MIC values of 0.39-1.56μg/mL against the tested bacterial strains and exhibited the most potent E. coli FabH inhibitory activity with IC50 of 5.2μM, being better than the positive control Kanamycin B with IC50 of 6.3μM. Furthermore, docking simulation was performed to position compound H(17) into the E. coli FabH active site to determine the probable binding conformation. This study indicated that compound H(17) has demonstrated significant E. coli FabH inhibitory activity as a potential antibacterial agent and provides valuable information for the design of E. coli FabH inhibitors.

Within the past years, many researches on the synthesis, structure-activity relationships (SAR), antitumor, antiinflammatory and anti-bacterial activities of the pyrazole derivatives have been reported. Several pyrazole derivatives possess important pharmacological activities and they have been proved useful materials in drug research. Pyrazole derivatives play an important role in antitumor agents because of their good inhibitory activity against BRAF(V600E), EGFR, telomerase, ROS Receptor Tyrosine Kinase and Aurora-A kinase. In addition, pyrazole derivatives also show good antiinflammatory and anti-bacterial activities. In this review, the bioactivities of the pyrazole derivatives mentioned above will be summarized in detail. We sincerely hope that increasing knowledge of the SAR and cellular processes underlying the bioactivity of pyrazole derivatives will be beneficial to the rational design of new generation of small molecule drugs.

A cytoplasmically inherited genetic element in yeast, [PSI+], was confirmed to be a prionlike aggregate of the cellular protein Sup35 by differential centrifugation analysis and microscopic localization of a Sup35-green fluorescent protein fusion. Aggregation depended on the intracellular concentration and functional state of the chaperone protein Hsp104 in the same manner as did [PSI+] inheritance. The amino-terminal and carboxy-terminal domains of Sup35 contributed to the unusual behavior of [PSI+]. [PSI+] altered the conformational state of newly synthesized prion proteins, inducing them to aggregate as well, thus fulfilling a major tenet of the prion hypothesis.

Eukaryotic cells extend a variety of surface protrusions to direct cell motility. Formation of protrusions is mediated by coordinated actions between the plasma membrane and the underlying actin cytoskeleton. Here, we found that the single calponin homology (CH) domain-containing protein CHDP-1 induces the formation of cell protrusions in C. elegans. CHDP-1 is anchored to the cortex through its amphipathic helix. CHDP-1 associates through its CH domain with the small GTPase Rac1/CED-10, which is a key regulator of the actin cytoskeleton. CHDP-1 preferentially binds to the GTP-bound active form of the CED-10 protein and preserves the membrane localization of GTP-CED-10. Hence, by coupling membrane expansion to Rac1-mediated actin dynamics, CHDP-1 promotes the formation of cellular protrusions in vivo., Author Summary In response to intra- and extracellular cues, remodeling of the sub-membranous cortical actin cytoskeleton constantly reorganizes the plasma membrane. Thus, distinct types of actin-rich invaginations or protrusions, such as filopodia and lamellipodia, enable cells to explore territory and pull themselves around. Extensive research has shown that the plasma membrane is tightly coupled to the motility machinery. However, how the continuous reorganization of the actin cytoskeleton is coupled with appropriate restructuring of the plasma membrane at the molecular level in vivo is unclear. Here, we identified that the single calponin homology (CH) domain-containing protein CHDP-1 promotes the formation of cell protrusions in C. elegans. CHDP-1 localizes to the cell cortex and through its calponin homology (CH) domain, CHDP-1 directly binds to the master actin regulator Rac1/CED-10 and enhances the membrane localization of the active CED-10 protein. Thus, we discovered a novel CHDP-1/Rac1 module which effectively couples membrane expansion to cortex actin dynamics in vivo.

Scathophaga stercoraria (Linnaeus, 1758) is a well-established insect model species involved in numerous investigations on behavior, biology, phylogeny, genetics and evolution. The antennal sensilla of S. stercoraria are examined via scanning electron microscopy in order to emphasize their importance on taxonomy and phylogeny. On antennal scape and pedicel, both microtrichiae and several sharp-tipped mechanoreceptors are observed, while another two structures, setiferous plaques and pedicellar button, are also detected on antennal pedicel. One type of sensory pit and four types of antennal sensilla, including trichoid sensilla, basiconic sensilla, coeloconic sensilla and clavate sensilla, are observed on antennal funiculus. Similarity and disparity of setiferous plaques among different calyptrate groups are analyzed in terms of phylogeny. The phylogenetic results supported by morphology of setiferous plaques strongly accord with the cladistic relations based on known molecular tree, implying the potential taxonomic and phylogenetic implications of the plaques in Calyptratae.

A series of novel 4,5-dihydropyrazole derivatives (3a-3t) containing hydroxyphenyl moiety as potential V600E mutant BRAF kinase (BRAF(V600E)) inhibitors were designed and synthesized. Docking simulation was performed to insert compounds 3d (1-(5-(5-chloro-2-hydroxyphenyl)-3-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) and 3m (1-(3-(4-chlorophenyl)-5-(3,5-dibromo-2-hydroxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)ethanone) into the crystal structure of BRAF(V600E) to determine the probable binding model, respectively. Based on the preliminary results, compound 3d and 3m with potent inhibitory activity in tumor growth may be a potential anticancer agent. Results of the bioassays against BRAF(V600E), MCF-7 human breast cancer cell line and WM266.4 human melanoma cell line all showed several compounds had potent activities IC(50) value in low micromolar range, among them, compound 3d and compound 3m showed strong potent anticancer activity, which were proved by that 3d: IC(50) = 1.31 μM for MCF-7 and IC(50) = 0.45 μM for WM266.5, IC(50) = 0.22 μM for BRAF(V600E), 3m: IC(50) = 0.97 μM for MCF-7 and IC(50) = 0.72 μM for WM266.5, IC(50) = 0.46 μM for BRAF(V600E), which were comparable with the positive control Erlotinib.

A series of novel chalcone derivatives have been designed and synthesized, and their biological activities were also evaluated as potential inhibitors of tubulin. These compounds were assayed for growth-inhibitory activity against MCF-7 and A549 cell lines in vitro. Compound 3d showed the most potent antiproliferative activity against MCF-7 and A549 cell lines with IC50 values of 0.03 and 0.95 μg/mL and exhibited the most potent tubulin inhibitory activity with IC50 of 1.42 μg/mL. Docking simulation was performed to insert compound 3d into the crystal structure of tubulin at colchicines binding site to determine the probable binding model. Based on the preliminary results, compound 3d with potent inhibitory activity in tumor growth may be a potential anticancer agent.

Identification of the primary tumour can prolong the life expectancy of patients with primary unknown cervical lymph node metastasis (PUCLNM) through targeted therapy. This study investigated the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET-CT) at identifying primaries in patients with PUCLNM.Twenty-seven patients (21 males and 6 females, median age 48.2 ± 16.3, age range 30-73) with PUCLNM underwent FDG PET-CT to search for the primary tumour, which could not be detected by conventional diagnostic modalities. The results were analysed and correlated with either pathological findings or clinical follow up.Pathological FDG uptake suspicious for the primary was detected in 13 cases, while the primary tumour remained occult in 14 cases. Eleven of 13 patients with suspected primaries were confirmed by histological findings. One with a coexisting second tumour and three with unexpected distant metastases were found in patients with confirmed primaries. The most common primary location in patients with PUCLNM found in our study was nasopharynx. In those 14 patients with negative FDG PET-CT results, only one patient had a primary malignancy that was proven histologically after endoscopy with biopsy during a period of clinical follow up. The sensitivity, specificity, accuracy and positive predictive values of FDG PET-CT were 91.7, 86.7, 88.9 and 84.6%, respectively.FDG PET-CT is a useful tool to help search for unknown primaries in patients with cervical lymph node metastasis and has an acceptable diagnostic yield for the detection of distant malignancies.

To study the effects of combinative therapy of tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and PI3-K-Akt inhibitor on the growth and apoptosis of nasopharyngeal carcinoma (NPC) cells and underlying mechanisms.With cell growth assay, flow cytometric analysis and Western blotting, the effects of TRAIL and PI3-K-Akt special inhibitor (LY294002) on cell growth, apoptosis and related proteins expressions in CNE-2 cell lines were studied.When concentrate of TRAIL1 ng/ml, viability rate of cells in combinative treatment group with TRAIL and LY294002 was higher than that in the single treatment group with TRAIL (all P0.05). When concentrate of TRAIL were 10 ng/ml and 100 ng/ml, the combinative treatment induced CNE-2 apoptosis more obviously than single treatments (t were 7.167 and 7.206, all P0.05). The combination group showed more cleavage of Caspase-8, Caspase-3, Caspase-9 than single treatment groups.Combinative application of TRAIL and PI3-K-Akt pathway inhibitor inhibits the growth of CNE-2 and induces apoptosis. The mitochondrial dependent pathway is implicated for the underlying mechanism.

Piper laetispicum C.DC. (Piperaceae), is an endemic climbing, glabrous plant distributed in the southern part of China. A novel alkaloid amide, Laetispicine, from it has been proven to possess antidepressant activity. In this present study, antidepressant and antinociceptive effects of the ethyl acetate extract (EAE) of P. laetispicum have been studied in forced swimming, open field, acetic acid writhing and formalin tests in KM mice. A significantly antidepressant-like effect was showing at doses of higher than 60 mg/kg, which was not due to an increase in locomotive activity. The EAE also presented an analgesic effect, in our studies. At lower doses (30 mg/kg) the antinociceptive effect was likely mediated via peripheral inflammation and changes in central processing, and at higher doses (120 mg/kg) that was due to both central and peripheral pathways. We also quantitatively analyzed the major components of EAE by HPLC and approached the structure-activity relationship between structure of amide alkaloids and its antidepressant activities. The antidepressant effective components of EAE might be Leatispiamide A and Laetispicine. In their molecular structures, the isolated double bond from benzene ring and conjugated double bond located at 2-3 and 4-5 were necessary for its antidepressant activity.

A novel class-specific molecularly imprinted polymer (MIP) beads for sulfonylurea herbicides was synthesized by precipitation polymerization using chlorsulfuron as the template molecule, 2-(diethylamino) ethyl methacrylate (DEAEMA) as the functional monomer, and trimethylolpropane trimethacrylate (TRIM) as the cross-linker. The mechanisms of recognition of MIP beads to the template molecule were evaluated by UV-spectrum and FTIR in the choosing and optimizing polymerization system experiment. The results showed that MIP beads contained the group which could interact with template molecule and its analogue by the hydrogen bonding specifically.