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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.

The use of nonlinear mechanical analysis in the optimization design process can achieve the precise numerical design of complex truss structures, which is a research hotspot and challenge in the field of structure optimization. To the complex truss structure, the new coordinated optimization method (COM) of customized non-uniform discrete variables (CV) coupling nonlinear mechanical analysis (CV-COM) is presented here. First, the variable coordination condition is embedded in the discrete variable direct search method by considering the coordination relationship between the parameters. Then, a complete CV-COM for engineering practice is formed, which is combined with the nonlinear finite element to provide implicit constraints for optimization. Finally, the truss structure was optimized through 14 design variables. The results show that optimized boom makes full use of the bearing capacity of the material and the optimization method of complex truss for engineering and the new method is effective.

Purpose: Paper-based artifacts hold significant cultural and social values. However, paper is intrinsically fragile to microorganisms, such as mold, due to its cellulose composition, which can serve as a microorganisms’ nutrient source. Mold not only can damage papers’ structural integrity and pose significant challenges to conservation works but also may subject individuals attending the contaminated artifacts to health risks. Current approaches for strain identification usually require extensive training, prolonged time for analysis, expensive operation costs, and higher risks of secondary damage due to sampling. Thus, in current conservation practices with mold-contaminated artifacts, little pre-screening or strain identification was performed before mold removal, and the cleaning techniques are usually broad-spectrum rather than strain-specific. With deep learning showing promising applications across various domains, this study investigated the feasibility of using a convolutional neural network (CNN) for fast in-situ recognition and classification of mold on paper. Methods: Molds were first non-invasively sampled from ancient Xuan Paper-based Chinese books from the Qing and Ming dynasties. Strains were identified using molecular biology methods and the four most prevalent strains were inoculated on Xuan paper to create mockups for image collection. Microscopic images of the molds as well as their stains situated on paper were collected using a compound microscope and commercial microscope lens for cell phone cameras, which were then used for training CNN models with a transfer learning scheme to perform the classification of mold. To enable involvement and contribution from the research community, a web interface that actuates the process while providing interactive features for users to learn about the information of the classified strain was constructed. Moreover, a feedback functionality in the web interface was embedded for catching potential classification errors, adding additional training images, or introducing new strains, all to refine the generalizability and robustness of the model. Results & Conclusion: In the study, we have constructed a suite of high-confidence classification CNN models for the diagnostic process for mold contamination in conservation. At the same time, a web interface was constructed that allows recurrently refining the model with human feedback through engaging the research community. Overall, the proposed framework opens new avenues for effective and timely identification of mold, thus enabling proactive and targeted mold remediation strategies in conservation.

Background Telbivudine (LdT) and tenofovir (TDF) are widely used in pregnant women to prevent vertical transmission; however, limited data are available on the differences in clinical efficacy and safety between the two drugs.Methods A total of 307 hepatitis B e antigen (HBeAg)-positive pregnant women with complete follow-up data were enrolled, the patients with alanine aminotransferase (ALT) levels <1xULN at baseline were enrolled to cohort 1 for treatment from 28 ±4 weeks gestation to delivery, while ALT levels >1xULN at baseline were enrolled to cohort 2 for treatment from 28 ±4 weeks gestation and continued after delivery. The clinical efficacy and safety was compared in LdT- and TDF-treated patients. In addition, 32 patients in cohort 1 were analysed for nucleoside analogue (NA)-related resistance mutations at baseline and after delivery.Results The results showed that HBV DNA levels were significantly lower at delivery than at baseline (P<0.001), but the decreases in HBV DNA, ALT, total bilirubin and total bile acid levels did not differ between the LdT- and TDF-treated patients at different time points (P>0.05) in the two cohorts. However, gastrointestinal adverse effects (vomiting) occurred more frequently in TDF-treated than LdT-treated patients (6.6% versus 0.0%; P=0.001). The results of NA-related resistance mutations analysis in cohort 1 revealed that short-term LdT or TDF treatment did not significantly change the NA-related resistance mutations (P>0.05).Conclusions This study revealed that the clinical efficacy in LdT- or TDF-treated HBeAg-positive Chinese pregnant women is similar, and gastrointestinal adverse effects occurred more frequently in TDF-treated patients.

Poor medication adherence is one of the leading causes of suboptimal glycaemic control in approximately half of the patients with type 2 diabetes mellitus (T2DM). Long-acting antidiabetic drugs are clinically needed for improving patients’ compliance. Dipeptidyl peptidase-4 (DPP-4) inhibitors play an increasingly important role in the treatment of T2DM because of their favorable properties of weight neutrality and hypoglycemia avoidance. Herein, we report the successful discovery and scale-up synthesis of compound 5, a structurally novel, potent, and long-acting DPP-4 inhibitor for the once-weekly treatment of T2DM. Inhibitor 5has fast-associating and slow-dissociating binding kinetics profiles as well as slow clearance rate and long terminal half-life pharmacokinetic properties. A single-dose oral administration of 5(3 mg/kg) inhibited >80% of DPP-4 activity for more than 7 days in diabetic mice. The long-term antidiabetic efficacies of 5(10 mg/kg, qw) were better than those of the once-weekly trelagliptin and omarigliptin, especially in decreasing the hemoglobin A1c level.

To exploit a bioactive material as components of functional products, juices from purple perilla; purple potato and blueberry were abstracted and concentrated. These concentrated juices were diluted to optimize the composition by evalustion of lavor. A bioactive material with 30% concentrated juice from purple perilla,50% from blueberry and 20% from purple potato, which contains 3.72% anthocyanin and shows antioxidant activity. This biomaterial can be use in processing functional products which have the functions of plant anthocyanin.

Metabotropic glutamate receptors (mGluRs) regulate neurogenesis in the mammalian central nervous system during development and throughout adulthood. However, the mechanisms remain unknown. The present study was aimed at investigating the effect of mGluR5 on the differentiation of rat neural progenitor cells (NPCs) into neurons as well as the underlying molecular mechanisms. NPCs were treated with mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), mGluR5 siRNA, and antagonist 6-methyl-2-(phenylethynyl) pyridine hydrochloride (MPEP), respectively. Three different subtypes of neurons (cholinergic, GABAergic, and dopaminergic neurons) were evaluated, and the activation of signaling pathways of mitogen-activated protein kinases was determined. Results showed that CHPG caused rat NPCs to differentiate into neurons, whereas mGluR5 siRNA and MPEP inhibited the cell differentiation. The proportion of cholinergic neurons increased with CHPG treatment and decreased after siRNA or MPEP treatment, whereas there were no significant changes in the proportions of GABAergic and dopaminergic neurons after treatment. The phosphorylated ERK12 levels increased after CHPG treatment and decreased after siRNA or MPEP treatment. In conclusion, our findings showed that mGluR5 caused rat NPCs to differentiate into cholinergic neurons by activating ERKs, suggesting that mGluR5 may play a significant role in the mechanism and treatment of degenerative diseases such as Alzheimer’s disease.

This paper use the different connection type of arterial roads and auxiliary road as the study subject, make the comparative analysis of traffic flow, traffic speed, distance of the import and export and ratio of weaving traffic flow in weaving area, then use the micro-simulation tool VISSIM to analysis the traffic volume and travel time of different connection type and offer related suggestions for their respective adaptability.

Introduction This study is aimed at the determination of the effect of the immune-regulatory factor NLRX1 on the antiviral activity of hepatocytes against an external stimuli favoring hepatitis B virus infection, and to explore its mechanism of action.Methods A HepG2-NTCP model was established using the LV003 lentivirus. Cells were transfected using an overexpression vector and NLRX1 siRNA to achieve overexpression and interference of NLRX1 expression (OV-NLRX1, si-NLRX1). Levels of HBsAg and HBcAg were determined using Western blotting analysis and immunohistochemical analysis. The levels of hepatitis B virus DNA and hepatitis B virus cccDNA were determined by real-time quantitative polymerase chain reaction. The expression and transcriptional activity of IFN-α, IFN-β, and IL-6 were measured using real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and promoter-luciferase reporter plasmids. Co-immunoprecipitation was used to determine the effect of NLRX1 on the interaction between MAVS and RIG-1. Western blotting was used to obtain the phosphorylation of essential proteins in the MAVS-RLRs signaling pathways.Results NLRX1 promoted HepG2-NTCP cell hepatitis B virus infection. Compared to the control group, the levels of HBsAg, HBcAg, hepatitis B virus cccDNA, and hepatitis B virus DNA increased in the OV-NLRX1 group and decreased in the si-NLRX1. Co-immunoprecipitation results showed that NLRX1 competitively inhibited the interaction between MAVS and RIG-1, and inhibited the phosphorylation of p65, IRF3, and IRF7. Additionally, NLRX1 reduced the transcription activity and expression levels of the final products: IFN-α, IFN-β, and IL-6.Conclusions NLRX1 can counteract innate immune response induced by an external stimuli favoring hepatitis B virus infection by competitive inhibition of MAVS-RLRs signaling in HepG2-NTCP cells. Inhibition of the MAVS-RLR-mediated signaling pathways leads to a decline in the expression levels of I-IFN and IL-6.