DESIGN, SYNTHESIS AND EVALUATION OF BIVALENT INHIBITORS OF TREHALOSE-6-PHOSPHATE PHOSPHATASE

The D-glucose disaccharide α, α-D-trehalose is synthesized by a variety of bacteria, fungi, plants and invertebrates to support cell survival by functioning as a fuel, a metabolic regulator or a protectant against environmental stress. Five different trehalose biosynthetic pathways are known to exist, one of which, the OtsA/OtsB pathway is common among pathogenic bacteria and fungi and is also found in parasitic nematodes. Previously reported otsA and otsB gene knockout (or knockdown) experiments have shown that both pathway enzymes are essential for M. tuberculosis cell growth and host colonization. RNAi gene silencing carried out in the nematode model system Caenohabditis elegans revealed that the T6P phosphatase is essential. Based on these findings we concluded that trehalose-synthesizing pathogens are likely to be vulnerable to the action of small molecule inhibitors of T6P phosphatase. We designed a bi-module inhibitor prototype. Accordingly, the phosphate group of the trehalose 6-phosphate moiety was replaced by a phosphate mimetic for targeting the active site of the catalytic domain, and the glucose unit was modified for targeting the cap domain for induced cap closure over the active site. Sulfate proved to be the most effective warhead for the substrate-binding site. T6S binding was shown by using Single Angle X-ray Scattering (SAXS) analysis to induce cap closure. Using glucose-6-sulfate as the platform, a series of synthetic derivatives possessing \u27drug-like\u27 functions tethered to the glucose ring were evaluated. Of these first generation inhibitors 4-n-octylphenyl-α-D-glucopyranoside 6-sulfate proved to be the tightest binding T6PP competitive inhibitor. In parallel, we have used the glucose-6-sulfate as the scaffold in the design of active site-directed, irreversible inhibitors. From the adducts which were synthesized and tested for T6PP inactivation, 4-n-octylphenyl-2-(3-(flurosulfonyl) benzoylamino)-2-deoxy-α-D-glucopyranoside-6-sulfate was selected for further characterization, and subsequently shown to inactivate the T6PPs with stoichiometric covalent modification and reasonable efficiency. Bioinformatic analysis and site-directed mutagenesis methods were used to identify the modified residue, a stringently conserved lysine residue was identified. Based on this result, the design and synthesis of the second generation of irreversible inhibitors that are optimized this target site is planned for future work

Energy Consumption Model of WSN Based on Manifold Learning Algorithm

Energy saving is one of the most important issues in wireless sensor networks. In order to effectively model the energy consumption -in wireless sensor network, a novel model is proposed based on manifold learning algorithm. Firstly, the components of the energy consumption by computational equations are measured, and the objective function is optimized. Secondly, the parameters in computational equations are estimated by manifold learning algorithm. Finally, the simulation experiments on OPNET and MATLAB Simulink are performed to evaluate the key factors influencing the model. The experimental results show that the proposed model had significant advantage in terms of synchronization accuracy and residual energy in comparison with other methods

Microstructural and Electron-Emission Characteristics of Nb-Si-N Films in Surface-Conduction Electron-Emitter Display

AbstractWe proposed ternary nitride Nb-Si-N film as a promising surface-conduction electron emitter (SCE) in surface-conduction electron-emitter display (SED). Nb-Si-N films consisted of continuous NbN polycrystalline phase with (Si3-xNb4x)N4 amorphous phase in NbN grain boundaries. After electroforming, serrated nanogaps were observed in Nb-Si-N SCE strips. The emission current of Nb-Si-N SCE array of 1×18 cells was 6.50μA with anode voltage of 1.5kV and device voltage of 22V, indicating satisfying potential for display applications comparing with NbN SCEs. © 2009 Published by Elsevier B.V

TIPE2 Suppresses Malignancy of Pancreatic Cancer Through Inhibiting TGFβ1 Mediated Signaling Pathway

Pancreatic cancer is one of the major reasons of cancer-associated deaths due to poor diagnosis, high metastasis and drug resistance. Therefore, it is important to understand the cellular and molecular mechanisms of pancreatic cancer to identify new targets for the treatment. TIPE2 is an essential regulator of tumor apoptosis, inflammation and immune homeostasis. However, the role of TIPE2 is still not fully understood in pancreatic cancer. In this study, we found the expression of TIPE2 was decreased in pancreatic cancer tissues compare to paracancerous tissues, which was negatively correlated with tumor size in patients. Overexpression of TIPE2 significantly decreased cell proliferation, metastasis and increased apoptotic events in pancreatic cancer cell lines. Moreover, the results obtained from real time PCR and western blot revealed that TIPE2 was also involved in inhibiting MMPs and N-Cadherin expression while increasing Bax expression in pancreatic cancer cells. Similarly, TIPE2 could inhibit tumor growth in vivo, decrease the expression of Ki-67 and N-Cadherin, and increase the expression of Bax by IHC analysis in tumor tissues isolated from tumor-bearing mice. Mechanistic studies exhibited that TIPE2 might suppress pancreatic cancer development through inhibiting PI3K/AKT and Raf/MEK/ERK signaling pathways triggered by TGFβ1. Moreover, the tumor-infiltrating lymphocytes from tumor-bearing mice were analyzed by flow cytometry, and showed that TIPE2 could promote T cell activation to exert an anti-tumor effect possibly through activation of DCs in a TGFβ1 dependent manner. In general, we described the multiple regulatory mechanisms of TIPE2 in pancreatic tumorigenesis and tumor microenvironment, which suggested TIPE2 may act as a potential therapeutic target in pancreatic cancer

Solid-state fermentation of Apocynum venetum L. by Aspergillus niger: Effect on phenolic compounds, antioxidant activities and metabolic syndrome-associated enzymes

This study aimed to evaluate the effect of solid-state fermentation (SSF) with Aspergillus niger on the total phenolic content (TPC), the total flavonoid content (TFC), individual phenolic contents, and antioxidant and inhibitory activities against metabolic syndrome-associated enzymes in an ethanol extract from Apocynum venetum L. (AVL). TPC, TFC, and the contents of quercetin and kaempferol during SSF were 1.52-, 1.33-, 3.64-, and 2.22-fold higher than those of native AVL in the ethyl acetate (EA) subfraction of the ethanol extract. The ABTS·+, DPPH· scavenging, and inhibitory activities against α-glucosidase and pancreatic lipase were found to be highest in the EA subfraction. Fermentation significantly increased the ABTS radical cation, DPPH radical scavenging, and pancreatic lipase inhibitory activities by 1.33, 1.39, and 1.28 times, respectively. TPC showed a significantly positive correlation with antioxidant activities or inhibition against metabolic syndrome-associated enzymes. This study provides a theoretical basis for producing tea products with enhanced antioxidant, antidiabetic, and antihyperlipidemic activities

The Time Course of the Influence of Valence and Arousal on the Implicit Processing of Affective Pictures

In the current study, we investigated the time course of the implicit processing of affective pictures with an orthogonal design of valence (negative vs. positive) by arousal (low vs. high). Previous studies with explicit tasks suggested that valence mainly modulates early event-related potential (ERP) components, whereas arousal mainly modulates late components. However, in this study with an implicit task, we observed significant interactions between valence and arousal at both early and late stages over both parietal and frontal sites, which were reflected by three different ERP components: P2a (100–200 ms), N2 (200–300 ms), and P3 (300–400 ms). Furthermore, there was also a significant main effect of arousal on P2b (200–300 ms) over parieto-occipital sites. Our results suggest that valence and arousal effects on implicit affective processing are more complicated than previous ERP studies with explicit tasks have revealed

Common variants in SOX-2 and congenital cataract genes contribute to age-related nuclear cataract

Nuclear cataract is the most common type of age-related cataract and a leading cause of blindness worldwide. Age-related nuclear cataract is heritable (h2 = 0.48), but little is known about specific genetic factors underlying this condition. Here we report findings from the largest to date multi-ethnic meta-analysis of genome-wide association studies (discovery cohort N = 14,151 and replication N = 5299) of the International Cataract Genetics Consortium. We confirmed the known genetic association of CRYAA (rs7278468, P = 2.8 × 10−16) with nuclear cataract and identified five new loci associated with this disease: SOX2-OT (rs9842371, P = 1.7 × 1

Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria

Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria

Landscape-Based Assessment of Urban Resilience and Its Evolution: A Case Study of the Central City of Shenyang

Urban resilience is increasingly considered a useful approach to accommodate uncertainties while achieving sustainability in urban systems, especially in the context of rapid urbanization and global environmental change. However, current research on the quantitative assessment of urban resilience is limited. This study introduces four proxies of urban resilience, i.e., diversity, connectivity, decentralization, and self-sufficiency, and the perspective of the urban landscape for the measurement of urban resilience and further guidance on planning practices by establishing connections between resilience potential and landscape characteristics. Using multi-source data and employing landscape-based analysis methods, urban resilience is investigated from 1995 to 2015 in the central city of Shenyang. The results indicate that the composition and configuration of the urban landscape changed significantly during this period, which had a great influence on urban resilience. The temporal and spatial evolution of urban resilience showed obviously directional preferences and an evident distance effect. Overall, the resilience level increased slightly, while the internal differences experienced a declining trend. The four characteristics can be deployed as practical principles to shape urban resilience. The adjustment and trade-offs of these aspects to enhance responsive structures and simultaneously maintain sustainable ecosystem services can be effective ways to realize long-term resilience