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11.
A. C. Hendrick 《CMAJ》1920,10(12):1122-1128
12.
Kornacker MG Lai Z Witmer M Ma J Hendrick J Lee VG Riexinger DJ Mapelli C Metzler W Copeland RA 《Biochemistry》2005,44(34):11567-11573
Beta-APP cleaving enzyme (BACE) is responsible for the first of two proteolytic cleavages of the APP protein that together lead to the generation of the Alzheimer's disease-associated Abeta peptide. It is widely believed that halting the production of Abeta peptide, by inhibition of BACE, is an attractive therapeutic modality for the treatment of Alzheimer's disease. BACE is an aspartyl protease, and there is significant effort in the pharmaceutical community to apply traditional design methods to the development of active site-directed inhibitors of this enzyme. We report here the discovery of a ligand binding pocket within the catalytic domain of BACE that is distinct from the enzymatic active site (i.e., an exosite). Peptides, initially identified from combinatorial phage peptide libraries, contain the sequence YPYF(I/L)P(L/I) and bind specifically to this exosite, even in the presence of saturating concentrations of active site-directed inhibitors. Binding of peptides to the BACE exosite leads to a concentration-dependent inhibition of proteolysis for APP-related, protein-based substrates of BACE. The discovery of this exosite opens new opportunities for the identification and development of novel and potentially selective small molecule inhibitors of BACE that act through exosite, rather than active site, binding interactions. 相似文献
13.
Eun SY O'Connor BP Wong AW van Deventer HW Taxman DJ Reed W Li P Blum JS McKinnon KP Ting JP 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(7):4271-4275
We recently identified expression of the semaphorin receptor, plexin-A1, in dendritic cells (DCs); however, its function in these cells remains to be elucidated. To investigate function and maximize physiological relevance, we devised a retroviral approach to ablate plexin-A1 gene expression using small hairpin RNA (shRNA) in primary bone marrow-derived DCs. We show that plexin-A1 localizes within the cytoplasm of immature DCs, becomes membrane-associated, and is enriched at the immune synapse in mature DCs. Reducing plexin-A1 expression with shRNA greatly reduced actin polarization as well as Rho activation without affecting Rac or Cdc42 activation. A Rho inhibitor, C3, also reduced actin polarization. These changes were accompanied by the near-ablation of T cell activation. We propose a mechanism of adaptive immune regulation in which plexin-A1 controls Rho activation and actin cytoskeletal rearrangements in DCs that is associated with enhanced DC-T cell interactions. 相似文献
14.
Obesity has been associated with altered cerebral functions including cognitive control. The stop signal task (SST) has been widely used to study cognitive control by producing high conflict stop trials among many low conflict go trials. Contrasting these stop trials with go trials provides a measure of saliency processing and response inhibition. By comparing functional magnetic resonance images of obese (BMI >30) and lean (BMI <22) females performing the SST, we observed differences in regional brain activations despite similar behavioral performance between groups. Specifically, lean females had greater activations in the insula, inferior parietal cortex, cuneus, and supplementary motor area than obese females during stop as compared to go trials. This difference was caused by diminished brain activations in obese females in stop as compared to go trials. Furthermore, the brain activations in these regions inversely correlated to BMI across subjects. These preliminary findings suggest altered neural processes of cognitive control in obesity. 相似文献
15.
Loei H Tan HT Lim TK Lim KH So JB Yeoh KG Chung MC 《Journal of proteome research》2012,11(3):1759-1772
Gastric cancer is the second leading cause of cancer deaths worldwide, and currently, there are no clinically relevant biomarkers for gastric cancer diagnosis or prognosis. In this study, we applied a 2D-LC-MS/MS based approach, in combination with iTRAQ labeling, to study the secretomes of the gastric cancer cell lines AGS and MKN7. By performing a comparative analysis between the conditioned media and the whole cell lysates, our workflow allowed us to differentiate the bona fide secreted proteins from the intracellular contaminants within the conditioned media. Ninety proteins were found to have higher abundance in the conditioned media as compared to the whole cell lysates of AGS and MKN7 cells. Using a signal peptide and nonclassical secretion prediction tool and an online exosome database, we demonstrated that up to 92.2% of these 90 proteins can be exported out of the cells by classical or nonclassical secretory pathways. We then performed quantitative comparisons of the secretomes between AGS and MKN7, identifying 43 differentially expressed secreted proteins. Among them, GRN was found to be frequently expressed in gastric tumor tissues, but not in normal gastric epithelia by immunohistochemistry. Sandwich ELISA assay also showed elevation of serum GRN levels in gastric cancer patients, particularly those with early gastric cancer. Receiver operating characteristic (ROC) curves analysis confirmed that serum GRN can provide diagnostic discriminations for gastric cancer patients. 相似文献
16.
Fine root heterogeneity by branch order: exploring the discrepancy in root turnover estimates between minirhizotron and carbon isotopic methods 总被引:6,自引:0,他引:6
Guo D Li H Mitchell RJ Han W Hendricks JJ Fahey TJ Hendrick RL 《The New phytologist》2008,177(2):443-456
Fine roots constitute a large and dynamic component of the carbon cycles of terrestrial ecosystems. The reported fivefold discrepancy in turnover estimates between median longevity (ML) from minirhizotrons and mean residence time (MRT) using carbon isotopes may have global consequences. Here, a root branch order-based model and a simulated factorial experiment were used to examine four sources of error. Inherent differences between ML, a number-based measure, and MRT, a mass-based measure, and the inability of the MRT method to account for multiple replacements of rapidly cycling roots were the two sources of error that contributed more to the disparity than did the improper choice of root age distribution models and sampling bias. Sensitivity analysis showed that the rate at which root longevity increases as order increases was the most important factor influencing the disparity between ML and MRT. Assessing root populations for each branch order may substantially reduce the errors in longevity estimates of the fine root guild. Our results point to the need to acquire longevity estimates of different orders, particularly those of higher orders. 相似文献
17.
18.
T. R. McClanahan V. Hendrick M. J. Rodrigues N. V. C. Polunin 《Coral reefs (Online)》1999,18(3):195-203
The consequences of macroalgal overgrowth on reef fishes and means to reverse this condition have been little explored. An
experimental reduction of macroalgae was conducted at a site in the Watamu Marine National Park in Kenya, where a documented
increase in macroalgal cover has occurred over the last nine years. In four experimental 10 m by 10 m plots, macroalgae were
greatly reduced (fleshy algal cover reduced by 84%) by scrubbing and shearing, while four similar plots acted as controls.
The numerical abundance in all fish groups except wrasses and macroalgal-feeding parrotfishes (species in the genera Calotomus and Leptoscarus) increased in experimental algal reduction plots. Algal (Sargassum) and seagrass (Thalassia) assays, susceptible to scraping and excavating parrotfishes, were bitten more frequently in the algal reduction plots one
month after the manipulation. Further, surgeonfish (Acanthurus leucosternon and A. nigrofuscus) foraging intensity increased in these algal reduction plots. The abundance of triggerfishes increased significantly in experimental
plots relative to control plots, but densities remained low, and an index of sea urchin predation using tethered juvenile
and adult Echinometra mathaei showed no differences between treatments following macroalgal reduction. Dominance of reefs by macrofleshy algae appears
to reduce the abundance of fishes, mostly herbivores and their rates of herbivory, but also other groups such as predators
of invertebrates (triggerfishes, butterflyfishes and angelfishes).
Accepted: 2 February 1999 相似文献
19.
Simon N. Haydar Chiara Ghiron Laura Bettinetti Hendrick Bothmann Thomas A. Comery John Dunlop Salvatore La Rosa Iolanda Micco Martina Pollastrini Joanna Quinn Renza Roncarati Carla Scali Michela Valacchi Maurizio Varrone Riccardo Zanaletti 《Bioorganic & medicinal chemistry》2009,17(14):5247-5258
Alpha 7 nicotinic acetylcholine receptor (α7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment associated with a variety of disorders including Alzheimer’s disease and schizophrenia. Alpha 7 nAChRs are expressed in brain regions associated with cognitive function, regulate cholinergic neurotransmission and have been shown to be down regulated in both schizophrenia and Alzheimer’s disease. Herein we report a novel, potent small molecule agonist of the alpha 7 nAChR, SEN12333/WAY-317538. This compound is a selective agonist of the α7 nAChR with excellent in vitro and in vivo profiles, excellent brain penetration and oral bioavailability, and demonstrates in vivo efficacy in multiple behavioural cognition models. The SAR and biological evaluation of this series of compounds are discussed. 相似文献
20.