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931.
Y Ye W Akers B Xu S Bloch C Odonkor S Achilefu 《Bioorganic & medicinal chemistry letters》2012,22(17):5405-5409
A new near-infrared fluorescent compound containing two cyclic RGD motifs, cypate-[c(RGDfK)](2) (1), was synthesized based on a carbocyanine fluorophore bearing two carboxylic acid groups (cypate) for integrin α(v)β(3)-targeting. Compared with its monovalent counterpart cypate-c(RGDfK) (2), 1 exhibited remarkable improvements in integrin α(v)β(3) binding affinity and tumor uptake in nude mice of A549. The results suggest that cypate-linked divalent ligands can serve as an important molecular platform for exploring receptor-targeted optical imaging and treatment of various diseases. 相似文献
932.
Chelliah MV Chackalamannil S Xia Y Eagen K Greenlee WJ Ahn HS Agans-Fantuzzi J Boykow G Hsieh Y Bryant M Chan TM Chintala M 《Bioorganic & medicinal chemistry letters》2012,22(7):2544-2549
Discovery of a novel nor-seco himbacine analog as potent thrombin receptor (PAR-1) antagonist is described. Despite low plasma level, these new analogs showed excellent ex vivo efficacy in the monkey platelet aggregation assay. A potent hydroxy metabolite generated in vivo was identified as the agent responsible for the ex vivo efficacy. Following this discovery, the metabolite series was optimized to obtain analogs that showed very good ex vivo efficacy along with excellent pharmacokinetic profile in c. monkey. 相似文献
933.
Skidmore J Atcha Z Boucherat E Castelletti L Chen DW Coppo FT Cutler L Dunsdon RM Heath BM Hutchings R Hurst DN Javed S Martin S Maskell ES Norton D Pemberton DJ Redshaw S Rutter R Sehmi SS Scoccitti T Temple HE Theobald P Ward RW Wilson DM 《Bioorganic & medicinal chemistry letters》2012,22(10):3560-3563
A series of α7 nicotinic acetylcholine receptor full-agonists with a 1,3,4-oxadiazol-2-amine core has been discovered. Systematic exploration of the structure-activity relationships for both α7 potency and selectivity with respect to interaction with the hERG channel are described. Further profiling led to the identification of compound 22, a potent full agonist showing efficacy in the novel object recognition model of cognition enhancement. 相似文献
934.
935.
Pislariu CI D Murray J Wen J Cosson V Muni RR Wang M A Benedito V Andriankaja A Cheng X Jerez IT Mondy S Zhang S Taylor ME Tadege M Ratet P Mysore KS Chen R Udvardi MK 《Plant physiology》2012,159(4):1686-1699
A Tnt1-insertion mutant population of Medicago truncatula ecotype R108 was screened for defects in nodulation and symbiotic nitrogen fixation. Primary screening of 9,300 mutant lines yielded 317 lines with putative defects in nodule development and/or nitrogen fixation. Of these, 230 lines were rescreened, and 156 lines were confirmed with defective symbiotic nitrogen fixation. Mutants were sorted into six distinct phenotypic categories: 72 nonnodulating mutants (Nod-), 51 mutants with totally ineffective nodules (Nod+ Fix-), 17 mutants with partially ineffective nodules (Nod+ Fix+/-), 27 mutants defective in nodule emergence, elongation, and nitrogen fixation (Nod+/- Fix-), one mutant with delayed and reduced nodulation but effective in nitrogen fixation (dNod+/- Fix+), and 11 supernodulating mutants (Nod++Fix+/-). A total of 2,801 flanking sequence tags were generated from the 156 symbiotic mutant lines. Analysis of flanking sequence tags revealed 14 insertion alleles of the following known symbiotic genes: NODULE INCEPTION (NIN), DOESN'T MAKE INFECTIONS3 (DMI3/CCaMK), ERF REQUIRED FOR NODULATION, and SUPERNUMERARY NODULES (SUNN). In parallel, a polymerase chain reaction-based strategy was used to identify Tnt1 insertions in known symbiotic genes, which revealed 25 additional insertion alleles in the following genes: DMI1, DMI2, DMI3, NIN, NODULATION SIGNALING PATHWAY1 (NSP1), NSP2, SUNN, and SICKLE. Thirty-nine Nod- lines were also screened for arbuscular mycorrhizal symbiosis phenotypes, and 30 mutants exhibited defects in arbuscular mycorrhizal symbiosis. Morphological and developmental features of several new symbiotic mutants are reported. The collection of mutants described here is a source of novel alleles of known symbiotic genes and a resource for cloning novel symbiotic genes via Tnt1 tagging. 相似文献
936.
Oreopithecus bambolii is a Late Miocene hominoid with an extensive fossil record in the Baccinello Basin (Tuscany, Italy), and was the only western European hominoid to survive a major extinction event ca. 9.6 Ma (millions of years ago). Oreopithecus lived in the insular Tusco-Sardinian paleobioprovince, where it evolved many unique anatomical specializations that make it important for understanding the mechanisms and history of Late Miocene hominoid evolution. The eventual extinction of Oreopithecus and its associated fauna ca. 6.5 Ma has generally been attributed to interaction with species that arrived from continental Europe following tectonic collision of the Tusco-Sardinian province with mainland Italy, but palynological, paleontological, and sedimentological records indicate an environmental shift toward more variable climate across the extinction event.To explore the possibility of environmental change as a contributing factor in the extinction of Oreopithecus, we developed a stable carbon and oxygen isotope record from organic matter in paleosols from the Baccinello Basin. These data show very low temporal and spatial variability (indicating plant ecosystem stability through time and space) and provide no evidence for ecologically significant changes in floral composition spanning the extinction event, suggesting that environmental change was not an underlying cause for the extinction of Oreopithecus and its associated fauna. The carbon isotope values fall entirely within the range of isotopic variability for modern plants following the C3 photosynthetic pathway (trees, shrubs, cool-season grasses), indicating that C4 vegetation (warm-season grasses) was not an important component of biomass. When corrected for temporal variation in the carbon isotopic composition of atmospheric carbon dioxide, the paleosol carbon isotope values are consistent with predicted values based on modern plants and the Baccinello palynoflora, supporting the reliability of paleosol isotopic records as paleoecological proxies. 相似文献
937.
Bell IM Stump CA Gallicchio SN Staas DD Zartman CB Moore EL Sain N Urban M Bruno JG Calamari A Kemmerer AL Mosser SD Fandozzi C White RB Zrada MM Selnick HG Graham SL Vacca JP Kane SA Salvatore CA 《Bioorganic & medicinal chemistry letters》2012,22(12):3941-3945
Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo. 相似文献
938.
Infection of mice with murine gammaherpesvirus 68 (MHV68) provides a tractable small animal model to study various aspects of persistent gammaherpesvirus infection. We have previously utilized a transgenic MHV68 that expresses enhanced yellow fluorescent protein (EYFP) to identify infected cells. While this recombinant MHV68 has been useful for identifying infected cell populations by flow cytometry, it has been suboptimal for identification of infected cells in tissue sections due to the high solubility of EYFP. Efficient detection of EYFP expressed from the MHV68 genome in tissue sections requires fixation of whole organs prior to sectioning, which frequently leads to over-fixation of some cellular antigens precluding their detection. To circumvent this issue, we describe the generation and characterization of a transgenic MHV68 harboring a fusion gene composed of the EYFP coding sequence fused to the histone H2B open reading frame. Because the H2bYFP fusion protein is tightly bound in nucleosomes in the nucleus it does not freely diffuse out of unfixed tissue sections, and thus eliminates the need for tissue fixation. We have used the MHV68-H2bYFP recombinant virus to assess the location and distribution of virus infected B cells in germinal centers during the peak of MHV68 latency in vivo. These analyses show that the physical location of distinct populations of infected germinal center B cells correlates well with their surface phenotype. Furthermore, analysis of the distribution of virus infection within germinal center B cell populations revealed that ca. 70% of MHV68 infected GC B cells are rapidly dividing centroblasts, while ca. 20% have a clear centrocyte phenotype. Finally, we have shown that marking of infected cells with MHV68-H2bYFP is extended long after the onset of latency - which should facilitate studies to track MHV68 latently infected cells at late times post-infection. 相似文献
939.
Stark JH Sharma R Ostroff S Cummings DA Ermentrout B Stebbins S Burke DS Wisniewski SR 《PloS one》2012,7(3):e34245
Background
Influenza is a contagious respiratory disease responsible for annual seasonal epidemics in temperate climates. An understanding of how influenza spreads geographically and temporally within regions could result in improved public health prevention programs. The purpose of this study was to summarize the spatial and temporal spread of influenza using data obtained from the Pennsylvania Department of Health''s influenza surveillance system.Methodology and Findings
We evaluated the spatial and temporal patterns of laboratory-confirmed influenza cases in Pennsylvania, United States from six influenza seasons (2003–2009). Using a test of spatial autocorrelation, local clusters of elevated risk were identified in the South Central region of the state. Multivariable logistic regression indicated that lower monthly precipitation levels during the influenza season (OR = 0.52, 95% CI: 0.28, 0.94), fewer residents over age 64 (OR = 0.27, 95% CI: 0.10, 0.73) and fewer residents with more than a high school education (OR = 0.76, 95% CI: 0.61, 0.95) were significantly associated with membership in this cluster. In addition, time series analysis revealed a temporal lag in the peak timing of the influenza B epidemic compared to the influenza A epidemic.Conclusions
These findings illustrate a distinct spatial cluster of cases in the South Central region of Pennsylvania. Further examination of the regional transmission dynamics within these clusters may be useful in planning public health influenza prevention programs. 相似文献940.