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Growth hormone secretagogue receptor 1a (GHS-R1a) is an important G protein-coupled receptor (GPCR) that regulates a variety of functions by binding to ghrelin. It has been shown that the dimerization of GHS-R1a with other receptors also affects ingestion, energy metabolism, learning and memory. Dopamine type 2 receptor (D2R) is a GPCR mainly distributed in the ventral tegmental area (VTA), substantia nigra (SN), striatum and other brain regions. In this study we investigated the existence and function of GHS-R1a/D2R heterodimers in nigral dopaminergic neurons in Parkinson’s disease (PD) models in vitro and in vivo. By conducting immunofluorescence staining, FRET and BRET analyses, we confirmed that GHS-R1a and D2R could form heterodimers in PC-12 cells and in the nigral dopaminergic neurons of wild-type mice. This process was inhibited by MPP+ or MPTP treatment. Application of QNP (10 μM) alone significantly increased the viability of MPP+-treated PC-12 cells, and administration of quinpirole (QNP, 1 mg/kg, i.p. once before and twice after MPTP injection) significantly alleviated motor deficits in MPTP-induced PD mice model; the beneficial effects of QNP were abolished by GHS-R1a knockdown. We revealed that the GHS-R1a/D2R heterodimers could increase the protein levels of tyrosine hydroxylase in the SN of MPTP-induced PD mice model through the cAMP response element binding protein (CREB) signaling pathway, ultimately promoting dopamine synthesis and release. These results demonstrate a protective role for GHS-R1a/D2R heterodimers in dopaminergic neurons, providing evidence for the involvement of GHS-R1a in PD pathogenesis independent of ghrelin.

Microcystin-leucine arginine (MC-LR) has reproductive and developmental toxicities. Previous studies indicated that gestational exposure to MC-LR induced fetal growth restriction in mice. The aim of this study was to further evaluate the effect of paternal MC-LR exposure before mating on fetal development. Male mice were intraperitoneally injected with either normal saline or MC-LR (10 μg/kg) daily for 35 days. Male mouse was then mated with female mice with 1:1 ratio. There was no significant difference on the rates of mating and pregnancy between MC-LR-exposed male mice and controls. Body weight and crown-rump length were reduced in fetuses whose fathers were exposed to MC-LR. Despite no difference on relative thickness of labyrinthine layer, cell proliferation, as measured by Ki67 immunostaining, was reduced in labyrinth layer of MC-LR-exposed mice. Moreover, blood sinusoid area in labyrinth layer was decreased in the fetus whose father was exposed to MC-LR before mating. Correspondingly, cross-sectional area of CD34-positive blood vessel in labyrinth layer was lower in fetuses whose fathers were exposed to MC-LR than in controls. These results provide evidence that paternal MC-LR exposure before mating induces fetal growth restriction partially through inhibiting cell proliferation and vascular development in labyrinth layer.

Several studies found that reduction of 5-hydroxymethylcytosine (5hmC), a marker of DNA hydroxymethylation highly enriched in developing brain, is associated with anxiety-like behaviors. This study aimed to investigate whether gestational arsenic (As) exposure induces anxiety-like behaviors in adult offspring by reducing DNA hydroxymethylation in the developing brain. The dams drank ultrapure water containing NaAsO2 (15 mg/L) throughout pregnancy. Anxiety-like behaviors were evaluated and developing brain 5hmC was detected. Results showed that anxiety-like behaviors were observed in As-exposed adult offspring. In addition, 5hmC content was reduced in As-exposed fetal brain. Despite no difference on Tet1, Tet2 and Tet3 expression, TET activity was suppressed in As-exposed fetal brain. Mechanistically, alpha-ketoglutarate (α-KG), a cofactor for TET dioxygenases, was reduced and Idh2, a key enzymatic gene for mitochondrial α-KG synthesis, was downregulated in As-exposed fetal brain. Of interest, ascorbic acid, a cofactor for TET dioxygenases, reversed As-induced suppression of TET activity. Moreover, ascorbic acid attenuated As-induced reduction of 5hmC in fetal brain. In addition, ascorbic acid alleviated As-induced anxiety-like behaviors in adult offspring. Taken together, these results suggest that gestational As exposure induces anxiety-like behaviors in adult offspring, possibly at part, by inhibiting DNA hydroxymethylation in developing brain.

ObjectiveType 2 diabetes mellitus is increasing in young adults, and greater adiposity is considered a major risk factor. However, whether there is an association between obesity and diabetes and how this might be impacted by age is not clear. Therefore, we investigated the association between body mass index (BMI) and diabetes across a wide range of age groups (20–30, 30–40, 40–50, 50–60, 60–70 and ≥70 years old).DesignWe performed a retrospective cohort study using healthy screening programme data.SettingA total of 211 833 adult Chinese persons >20 years old across 32 sites and 11 cities in China (Shanghai, Beijing, Nanjing, Suzhou, Shenzhen, Changzhou, Chengdu, Guangzhou, Hefei, Wuhan, Nantong) were selected for the study; these persons were free of diabetes at baseline.Primary and secondary outcome measuresFasting plasma glucose levels were measured and information regarding the history of diabetes was collected at each visit. Diabetes was diagnosed as fasting plasma glucose ≥7.00 mmol/L and/or self-reported diabetes. Patients were censored at the date of diagnosis or the final visit, whichever came first.ResultsWith a median follow-up of 3.1 years, 4174 of the 211 833 participants developed diabetes, with an age-adjusted incidence rate of 7.35 per 1000 persons. The risk of incident diabetes increased proportionally with increasing baseline BMI values, with a 23% increased risk of incident diabetes with each kg/m2increase in BMI (95% CI 1.22 to 1.24). Across all age groups, there was a linear association between BMI and the risk of incident diabetes, although there was a stronger association between BMI and incident diabetes in the younger age groups (age×BMI interaction, pConclusionsAn increased BMI is also independently associated with a higher risk of developing diabetes in young adults and the effects of BMI on incident diabetes were accentuated in younger adults.

An amorphous Ni-Fe-P alloy coated shielding fabric with dense uniform coating was prepared by conducting electrical deposition of amorphous Ni-Fe-P alloy on copper-coated polyethylene terephthalate (PET) fabric. This research investigated the preparation process by using orthogonal test with 8 factors and 3 levels. It analyzed the influences of components of the plating solution on the ohms per square, weight gain rate, and shielding effectiveness of coating. Besides, the morphology, composition, and structure of the coating were analyzed by using Scanning Electron Microscope (SEM), Energy Dispersive Spectrdmeter (EDS), and X-ray Diffraction (XRD). The shielding effectiveness of the alloy fabric was also tested. The results indicated that the processing conditions of the amorphous Ni-Fe-P alloy coated fabric using electrical deposition consisted of 135 g/L of NiSO4•6H2O, 105 g/L of FeSO4•7H2O, 8 g/L of NaH2PO2•H2O, 24 g/L of C6H8O6, 36 g/L of C6H8O7, 22 g/L of H3PO3, 65°C, pH=1.5, and current density =13 A/dm2. The fabric obtained in the paper presented compact, smooth, and uniform coating with fine crystal. The coating was the amorphous Ni-Fe-P alloy with 18.67% of P (mass fraction). The shielding effectiveness of this coated fabric reached to 60.82 dB-73.63 dB in a broad frequency range of 300 kHz-1.5 GHz.

Yin-zhi-huang (YZH) injection is an injectable multi-herbal prescription derived from the ancient Chinese medicine formula of Yin-chen-hao-tang, which is widely used in the clinic for the treatment of jaundice and chronic liver diseases. To date, the systematic study of the components in this multi-herbal prescription is still challenged by desirable analytical methods, by which a big array of components could be simultaneously detected at low concentrations. Herein, a new liquid chromatography- tandem mass spectrometry (LC-MS/MS) method by using dynamic multiple reaction monitoring (DMRM) mode was developed to determine multiple peaks in traditional Chinese medicine (TCM) preparation YZH injection. This simple, selective and sensitive method enabled the quantification of 22 components with standard materials with the lower limit of quantification (LLOQ) of 1.46-12.5 ng/mL in cell lysates. This method was successfully applied to celluar uptake and/or binding investigation of components in YZH injection. The results indicated that this strategy might be a useful approach for rapidly screening of the potential bioactive candidates from YZH injection, and the discovered candidates would be used to investigate the pharmacodynamics in the further study.

Non-motor symptoms, including pain, depression, sleep disorder, and olfactory dysfunction, occur frequently in patients with Parkinson’s disease (PD), even before the onset of motor symptoms. Although studies have examined the correlation between pain and depression or sleep disorder in PD, few studies have investigated the correlation between pain and a range of other non-motor symptoms of PD. PD patients (n = 142) with or without pain were included in the study. PD severity was evaluated with the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Hoehn and Yahr (H/Y) staging scale. Pain severity was analyzed with the Visual Analog Scale. The Hamilton Rating Scale for Depression (HRSD; 24 items), Montreal Cognitive Assessment Beijing Version (MoCA), and non-motor questionnaire (NMSQT) measured symptoms of depression, cognitive function, and non-motor symptoms. The incidence of pain was 47.9 % in patients with PD, most of whom had moderate pain levels. Patients with pain showed higher HRSD, UPDRS, H/Y, and NMSQT scores and lower MoCA scores compared to those of patients without pain. HRSD and NMSQT scores were closely related with pain (P < 0.001). Non-motor symptoms were more prominent in patients with pain compared to that of controls and PD patients without pain.

The maltose transporter from Escherichia coli is one of the ATP-binding cassette (ABC) transporters that utilize the energy from ATP hydrolysis to translocate substrates across cellular membranes. Until 2011, three crystal structures have been determined for maltose transporter at different states in the process of transportation. Here, based on these crystal structures, the allosteric pathway from the resting state (inward-facing) to the catalytic intermediate state (outward-facing) is studied by applying an adaptive anisotropic network model. The results suggest that the allosteric transitions proceed in a coupled way. The closing of the nucleotide-binding domains occurs first, and subsequently this conformational change is propagated to the transmembrane domains (TMD) via the EAA and EAS loops, and then to the maltose-binding protein, which facilitates the translocation of the maltose. It is also found that there exist nonrigid-body and asymmetric movements in the TMD. The cytoplasmic gate may only play the role of allosteric propagation during the transition from the pretranslocation to outward-facing states. In addition, the results show that the movment of the helical subdomain towards the RecA-like subdomain mainly occurs in the earlier stages of the transition. These results can provide some insights into the understanding of the mechanism of ABC transporters.

In this paper, aiming at the poor performance of the existing symbol rate estimation methods when SNR is low, we proposed a method based on the timing square which can be simply calculated and applied to MASK/MPSK/MQAM modulated signal, improved the performance of signal symbol rate estimation compared with the existing method. Based on the principle of the timing square, the signal modules were squared to calculate the fourier coefficient modulus corresponding to different sampling ratios. Then the characteristic line was searched in the transform spectrum which contains symbol rate information and obtained an estimation of the symbol rate. The impact of the roll-off factor and the carrier wave was analyzed and solution was proposed in this paper. Simulation results show that the performance of symbol rate estimation of the improved method is better than the original method, the wavelet transform method and the cyclostationary method in low SNR and low roll-off factor environment.

The collision that between a car and a train is the main type of accidents in the case railway level-crossing, which is proved by the arrangement diagram analysing. The fault tree analysis and the event tree analysis are used to assess the level of the risk of the level-crossing quantificationally. Some conclusions can be drawn: the collision of the railway level-crossing that between a car and a train will happen 2.552 in a year, which can bring 0.061 equivalent fatalities. This paper puts forward some precautionary measures that based on the minimal cut set of the collision of the accident and the most probable or the highest risk event.

Nearly 40% of Chinese water pollution comes from agricultural sources of pollution, and the annual emissions are difference. If we want to control pollution emissions effectively, we need to accurately predict the amount of agricultural emissions of Ammonia Nitrogen (AN) and Chemical Oxygen Demand (COD). Due to the complex mechanism of the agricultural non-point source pollution, its emissions are very difficult to measure. Currently, the Bionics Research is in a stage of rapid development, and it continues to expand into many new areas of research. So the comprehensive study of Bionics and pollutant control study will be a good choice. This research used bionic BP（Back Propagation） neural network algorithm, and used pollution census data from 2002 to 2007 and established neural network model with neural network algorithm. And we predicted the agricultural sources of emissions of AN and COD with the data from 2008 to 2010. Finally we compared the predicted value and the actual value. Research results showed that, with using the bionic BP neural network, agricultural sources emissions of AN and COD are evaluated actually and the results indicate that the average error is under 5.0%. Research results proved that the model is effective. The neural network is a scientific predict method for the agricultural sources emissions of AN and COD. It can be widely used in the prediction of agricultural sources emissions of AN and COD.

In this article, we try to find out the reasons of urban water logging . We will pay attention to the generation process, the affecting factors, and then seek the end solutions to solve the embarrassing situation.

To improve energy harvesting performance, a resonance frequency tunable piezoelectric (PZT) energy harvester for vibrating applications was presented and investigated experimentally. A piezoelectric vibrational energy harvester (PVEH) consisted of a piezo-cantilever with a permanent magnet at its free-end and another excitation magnet fixed on vibration structure. The two magnets are placed with the same magnetic poles facing each other to produce repulsive force. The cantilever has dimensions of 70x10x0.6mm3, clamped 10mm, and two magnets sized ø10x4mm3. The testing results show that the magnetic force, denoted by the initial separated distance between the magnetic dipoles (SDMD), exerts great influence on the generated performance. With the SDMD increasing from 15mm to 40mm, the generated voltage rises from 24.4V to 40V, and the resonant frequency increases from 33.75Hz to 38.75Hz.

Due to the concrete self-shrinkage, frequent load application and temperature fluctuation, and so on，the gap formed between the inner tube wall and the core concrete surfaces would decrease the performance of concrete-filled steel tube (CFST). To prevent this cavity problem, various types of expansive agents and aggregates were used in this study to improve the volume stability of core concrete. Comparative experiments with mortars and concrete were carried out respectively under standard curing condition and under enclosed curing condition which simulated the environment in steel tube. The results could be summarized as follows: ● Two types of expansive agents, ZY type expansive agent mainly containing sulfates and aluminates and M type expansive agent mainly containing magnesium oxide, presented different expansive behaviors with curing ages in mortar and concrete. Two types of expansive agents combined with each other could produce complementary and superimposition effects to improve continuously the volume stability of mortar and concrete. ● Sufficient water supply is the key factor for the formation and maintenance of expansion. The volume change caused by the self-shrinkage effect of core concrete could not be effectively off-set with whether two types expansive agents or their compounds under enclosed environment in which water was scarce and could not be supplied from outside. ● When some water-saturated ceramsite were used to partially replace aggregates in core concrete,the volume expansion performance of core concrete improved dramatically with the water storage and supply effects of water-saturated ceramsite.

BACKGROUND Transcription factors hypoxia inducible factor 1alpha (HIF 1alpha) and endothelial PAS domain protein 1 (EPAS1) promote the transcription of vascular endothelial growth factor (VEGF). VEGF enhances angiogenesis and vascular permeability of tumours, which promotes tumour growth and facilitates entry of cancer cells into blood circulation and metastasizing. This study examined whether HIF 1alpha and EPAS1 stimulated angiogenesis through activation of VEGF in human pancreatic carcinoma. METHODS Specimens from pancreatic carcinoma and healthy parts of same pancreas were taken from 60 patients. Real time quantitative reverse transcription polymerase chain reaction estimated expression of HIF 1alpha, EPAS1, and VEGF mRNAs. Western blotting and immunohistochemical, streptavidin peroxidase method assessed expression of HIF 1alpha, EPAS1, and VEGF proteins. Microvessel density (MVD) was assessed. RESULTS Highly significant increases in expression of EPAS1, VEGF, and MVD were found in pancreatic carcinoma tissue but not in normal pancreatic tissue: VEGF at mRNA and protein levels (t = 17.32, P = 0.0001; t = 98.41, P = 0.0001); EPAS1 protein level (t = 22.51, P = 0.0001). Expression of HIF 1alpha was similar in pancreatic carcinoma and normal pancreatic tissues at both mRNA and protein levels. Significant correlations were observed between EPAS1 and VEGF (r = 0.736, P = 0.0041), between VEGF and MVD (r = 0.858, P = 0.0001), and between EPAS1 and MVD (r = 0.641, P = 0.0003). No significant correlations were observed between HIF 1alpha and VEGF, or between HIF 1alpha and MVD. MVD and expression of EPAS1 and VEGF were significantly related with TNM staging, so was EPASI and VEGF with size of tumour. CONCLUSIONS EPAS1 and VEGF, but not HIF1alpha, are overexpressed in pancreatic carcinoma. The expression of EPAS1 is correlated with that of VEGF and MVD. EPAS1 may be involved in the angiogenesis of pancreatic carcinoma by upregulating the expression of VEGF. Targeting EPAS1 may be a new method of antiangiogenic tumour therapy for pancreatic carcinoma.

To develop a high-throughput real-time assay based on molecular beacons to monitor the integrase 3'-processing reaction in vitro and apply it to inhibitor screening.The recombinant human immunodeficiency virus (HIV)-1 integrase (IN) is incubated with a 38 mer oligonucleotide substrate, a sequence identical to the U5 end of HIV-1 long terminal repeats (LTR). Based on the fluorescence properties of molecular beacons, the substrate is designed to form a stem-loop structure labeled with a fluorophore at the 5' end and a quencher at the 3' end. IN cleaves the terminal 3'-dinucleotide containing the quencher, resulting in an increase in fluorescence which can be monitored on a spectrofluorometer. To optimize this assay, tests were performed to investigate the effects of substrates, enzyme and the metal ion concentrations on the IN activity and optimal parameters were obtained. Moreover, 2 IN inhibitors were employed to test the performance of this assay in antiviral compound screening.The fluorescent intensity of the reaction mixture varies linearly with time and is proportional to the velocity of the 3'-processing reaction. Tests were performed and the results showed that the optimal rate was obtained for a reaction mixture containing 50 mg/L recombinant HIV-1 IN, 400 nmol/L substrate, and 10 mmol/L Mn(2+). The IN 3'-processing reaction under the optimal conditions showed a more than 18-fold increase in the fluorescence intensity compared to the enzyme-free control. The IC50 values of the IN inhibitors obtained in our assay were similar to the values obtained from a radiolabeled substrate assay.Our results demonstrated that this is a fast, reliable, and sensitive method to monitor HIV IN 3'-processing reaction and that it can be used for inhibitor screening.

Integrase is an essential enzyme in the life cycle of Human immunoficiency virus type 1 (HIV-1) and also an important target for designing integrase inhibitors. In this paper, the binding modes between the wild type integrase core domain (ICD) and the W131A mutant ICD with the benzoic acid derivative--D77 were investigated using the molecular docking combined with molecular dynamics (MD) simulations. The result of MD simulations showed that the W131A substitution affected the flexibility of the region 150-167 in both the monomer A and B of the mutant type ICD. In principle, D77 interacted with the residues around the Lens Epithelium-Derived Growth Factor (LEDGF/p75) binding site which is nearby the HIV-1 integrase dimer interface. However, the specific binding modes for D77-wild type integrase and D77-mutant integrase systems are various. According to the binding mode of D77 with the wild type ICD, D77 can effectively intervene with the binding of LEDGF/p75 to integrase due to a steric hindrance effect around the LEDGF/p75 binding site. In addition, we found that D77 might also affect its inhibitory action by reducing the flexibility of the region 150-167 of integrase. Through energy decomposition calculated with the Molecular Mechanics Generalized Born Surface Area approach to estimate the binding affinity, it seems likely that W131 and E170 are indispensable for the ligand binding, as characterized by the largest binding affinity. All the above results are consistent with the experimental data, providing us with some helpful information not only for the understanding of the mechanism of this kind of inhibitor but also for the rational drug design.