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991.
992.
Alexey Rivkin Sean P. Ahearn Stephanie M. Chichetti Christopher L. Hamblett Yudith Garcia Michelle Martinez Jed L. Hubbs Michael H. Reutershan Matthew H. Daniels Phieng Siliphaivanh Karin M. Otte Chaomin Li Andrew Rosenau Laura M. Surdi Joon Jung Bethany L. Hughes Jamie L. Crispino George N. Nikov Richard E. Middleton Christopher M. Moxham Mark S. Shearman 《Bioorganic & medicinal chemistry letters》2010,20(7):2279-2282
The development of a novel series of purines as γ-secretase modulators for potential use in the treatment of Alzheimer’s disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based γ-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Αβ42 in an APP-YAC transgenic mouse model. 相似文献
993.
Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents
Saleem Ahmad Khehyong Ngu Keith J. Miller Ginger Wu Chen-pin Hung Sarah Malmstrom Ge Zhang Eva O’Tanyi William J. Keim Mary Jane Cullen Kenneth W. Rohrbach Michael Thomas Thao Ung Qinling Qu Jinping Gan Rangaraj Narayanan Mary Ann Pelleymounter Jeffrey A. Robl 《Bioorganic & medicinal chemistry letters》2010,20(3):1128-1133
Agonists of the 5-HT2C receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT2B receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT2C agonists with no detectable agonism of the 5-HT2B receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing. 相似文献
994.
Matthew G. Stanton Jed Hubbs David Sloman Christopher Hamblett Paula Andrade Minilik Angagaw Grace Bi Regina M. Black Jamie Crispino Jonathan C. Cruz Eric Fan Georgia Farris Bethany L. Hughes Candia M. Kenific Richard E. Middleton George Nikov Peter Sajonz Sanjiv Shah Nirah Shomer Alexander A. Szewczak Benito Munoz 《Bioorganic & medicinal chemistry letters》2010,20(2):755-758
We report herein a novel series of difluoropiperidine acetic acids as modulators of γ-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective β-difluorination with Selectfluor®. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Aβ42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250 mg/kg per day, AUC0–24 = 2100 μM h) did not exhibit Notch-related effects. 相似文献
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996.
997.
When cells are exposed to radiation serious lesions are introduced into the DNA including double strand breaks (DSBs), single strand breaks (SSBs), base modifications and clustered damage sites (a specific feature of ionizing radiation induced DNA damage). Radiation induced DNA damage has the potential to initiate events that can lead ultimately to mutations and the onset of cancer and therefore understanding the cellular responses to DNA lesions is of particular importance. Using γH2AX as a marker for DSB formation and RAD51 as a marker of homologous recombination (HR) which is recruited in the processing of frank DSBs or DSBs arising from stalled replication forks, we have investigated the contribution of SSBs and non-DSB DNA damage to the induction of DSBs in mammalian cells by ionizing radiation during the cell cycle. V79-4 cells and human HF19 fibroblast cells have been either irradiated with 0–20 Gy of γ radiation or, for comparison, treated with a low concentration of hydrogen peroxide, which is known to induce SSBs but not DSBs. Inhibition of the repair of oxidative DNA lesions by poly(ADP ribose) polymerase (PARP) inhibitor leads to an increase in radiation induced γH2AX and RAD51 foci which we propose is due to these lesions colliding with replication forks forming replication induced DSBs. It was confirmed that DSBs are not induced in G1 phase cells by treatment with hydrogen peroxide but treatment does lead to DSB induction, specifically in S phase cells. We therefore suggest that radiation induced SSBs and non-DSB DNA damage contribute to the formation of replication induced DSBs, detected as RAD51 foci. 相似文献
998.
Jatinder Kaur Mukker Valeriya Kotlyarova Ravi Shankar Prasad Singh Jane Alcorn 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》2010,878(30):3076-3082
We report a rapid and simple HPLC method with fluorescence detection for the quantification of the major flaxseed lignan, secoisolarisiresinol diglucoside (SDG) and its major metabolites. The method is specific for SDG, secoisolarisiresinol (SECO), enterodiol (ED) and entrolactone (EL) in rat serum. The assay procedure involves chromatographic separation using a Waters Symmetry C18 reversed-phase column (4.6 mm × 150 mm, 5 μm) and mobile phase gradient conditions consisting of acetonitrile (0.1% formic acid) and water (0.1% formic acid). SDG extraction from serum requires the use of Centrifuge filters while SECO, ED and EL are extracted with diethyl ether. The organic layer is evaporated and reconstituted in 100 μL of mobile phase and 50 μL of reconstituted sample or filtrate is injected onto the column. Total run time is 25 min. Calibration curves are linear (r2 ≥ 0.997) from 0.05 to 10 μg/mL for SDG and EL and 0.01–10 μg/mL for SECO and ED. Precision and accuracy are within USFDA specified limits. The stability of all lignans is established in auto-injector, bench-top, freeze–thaw and long-term stability at −80 °C for 30 days. The method's reasonable sensitivity and reliance on more widely available HPLC technology should allow for its straightforward application to pharmacokinetic evaluations of lignans in animal model systems such as the rat. 相似文献
999.
Duccio Rocchini Niko Balkenhol Gregory A. Carter Giles M. Foody Thomas W. Gillespie Kate S. He Salit Kark Noam Levin Kelly Lucas Miska Luoto Harini Nagendra Jens Oldeland Carlo Ricotta Jane Southworth Markus Neteler 《Ecological Informatics》2010,5(5):318-329
Environmental heterogeneity is considered to be one of the main factors associated with biodiversity given that areas with highly heterogeneous environments can host more species due to their higher number of available niches. In this view, spatial variability extracted from remotely sensed images has been used as a proxy of species diversity, as these data provide an inexpensive means of deriving environmental information for large areas in a consistent and regular manner. The aim of this review is to provide an overview of the state of the art in the use of spectral heterogeneity for estimating species diversity. We will examine a number of issues related to this theme, dealing with: i) the main sensors used for biodiversity monitoring, ii) scale matching problems between remotely sensed and field diversity data, iii) spectral heterogeneity measurement techniques, iv) types of species taxonomic diversity measures and how they influence the relationship between spectral and species diversity, v) spectral versus genetic diversity, and vi) modeling procedures for relating spectral and species diversity. Our review suggests that remotely sensed spectral heterogeneity information provides a crucial baseline for rapid estimation or prediction of biodiversity attributes and hotspots in space and time. 相似文献
1000.
This article seeks to investigate the association between caregiving to someone with an HIV-related illness and the socioeconomic status of the caregiver using a population-based survey of 1,587 older people living in Nairobi slums. Findings indicate significant differences in living arrangements, wealth, income, and expenditure between HIV caregivers and noncaregivers. HIV caregivers lived in larger households and were also more likely to live in households with a large number of children younger than the age of 15 years. Whereas a high proportion of HIV caregivers were ranked highly in terms of wealth status, differences in per capita income and expenditure were not significant when household size and other confounders were accounted for. The financial costs associated with caring for someone with a chronic illness and the reliance on family members with financial ability for material support, a common feature of African extended family systems, may account for the relative economic advantage of HIV caregivers. 相似文献